CN1085907A - New sulphur substituted nitrogen-containing heterocyclic phosphinic acid compounds, the method for pharmaceutical composition and treatment calcium and phosphoric acid salt abnormal metabolism - Google Patents

New sulphur substituted nitrogen-containing heterocyclic phosphinic acid compounds, the method for pharmaceutical composition and treatment calcium and phosphoric acid salt abnormal metabolism Download PDF

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CN1085907A
CN1085907A CN93108277A CN93108277A CN1085907A CN 1085907 A CN1085907 A CN 1085907A CN 93108277 A CN93108277 A CN 93108277A CN 93108277 A CN93108277 A CN 93108277A CN 1085907 A CN1085907 A CN 1085907A
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CN1039327C (en
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S·M·卡斯
F·H·艾贝丁诺
M·D·弗朗西斯
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Warner Chilcott Pharmaceuticals Inc
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Abstract

The present invention relates to the nitrogenous heterocyclic phosphinic acid compounds that sulphur replaces, comprise diphosphonate (or ester), phosphine acyl-alkyl phosphonate (or ester) phosphono-carboxylic acids salt (or ester), phosphono sulfonate (or ester) but and the salt of their patent medicine or ester.The invention still further relates to the compound of the present invention that comprises safe and effective amount and the pharmaceutical composition of pharmaceutically-acceptable excipients.At last, the invention still further relates to the mankind or other Mammals calcium and phosphatic abnormal metabolism is the treatment or the prevention method of the pathological conditions of feature, comprises treatment or preventing osteoporosis disease and sacroiliitis, particularly rheumatoid arthritis and osteoarthritis disease.This method comprises human or other Mammals administration of needs being treated with the The compounds of this invention of safe and effective amount or composition.The general structural formula of these compounds as above.

Description

New sulphur substituted nitrogen-containing heterocyclic phosphinic acid compounds, the method for pharmaceutical composition and treatment calcium and phosphoric acid salt abnormal metabolism
The present invention relates to new nitrogenous, heterocycle phosphinic acid compounds that sulphur replaces, comprise diphosphonate (or ester), phosphine acyl-alkyl phosphinates (or ester), phosphono-carboxylic acids salt (or ester) and phosphono sulfonate (or ester).The invention still further relates to the pharmaceutical composition that comprises these new compounds, relating to employing compound of the present invention or medicine composite for curing and prevention is the method for some metabolic bone disease of feature with calcium and phosphatic abnormal metabolism.Particularly, the present invention relates to adopt the particularly method of rheumatoid arthritis and osteoarthritis of compound of the present invention or medicine composite for curing or preventing osteoporosis disease and sacroiliitis.
The pathological condition of many puzzlement warm-blooded animals is all relevant with phosphatic abnormal metabolism with calcium.These illnesss roughly can be divided into two classes:
1. be the illness of feature with calcium and phosphatic abnormal movement, cause general or special bone loss, as osteoporosis and Paget's disease; Or cause the calcium of superelevation amount in the body fluid, as cause the hypercalcemia of tumour.This kind pathological condition is called as pathologic sclerous tissues demineralization in this article sometimes.
2. cause or cause calcium and the phosphoric acid salt pathological condition of abnormal deposition in vivo, as rheumatoid arthritis and osteoarthritis.These pathological conditions are referred to as pathologic calcification in this article sometimes.
The first kind comprises prevailing metabolic bone disease, and osteoporosis, osteoporosis are the forfeitures of a kind of bone sclerous tissues and the out-of-proportion pathological condition of formation of new sclerous tissues.The amount that osteoporosis generally can be defined as bone reduces or bone tissue's atrophy.It is big that marrow and bone space become, and fibrillar connective tissue reduces, and fine and close bone becomes fragile.Osteoporosis can be divided into several classes again: menopause osteoporosis, senile osteoporosis, drug-induced osteoporosis (as: adrenocortical steroid takes place when steroid therapy); (sacroiliitis and tumour) osteoporosis that disease causes etc.; But its The apparent phenomenon is basic identical.In general, two types osteoporosis is arranged, the firsts and seconds osteoporosis.The secondary osteoporosis is caused by isolating discernible lysis or medicament.But about 90% is " one-level osteoporosis " in all osteoporosis cases.This one-level osteoporosis comprises: postmenopausal osteoporosis, disuse osteoporosis, age related osteoporosis (can influence most of people that year order surpasses 70-80 year) and idiopathic osteoporosis disease (middle aged or young man and the women of influence).
For osteoporotic patient, the osseous tissue loss is too many so that cause that the mechanicalness of bone structure fails.For example, suffers from the women of post-menopausal osteoporosis through regular meeting's generation hip and spinal fracture.Often also can cause kyphosis (the chest spinal curvature will increases unusually).
The mechanism of bone loss it is believed that relevant with " bone reconstruction " process imbalance in the osteoporosis.Bone is rebuild all one's life of running through the people, realizes that bone upgrades and the maintenance bone strength.This process of reconstruction comprises the erosion of the loose part of bone surface and replenishes that this process is finished by the cell tissue that is called as " basic many cells unit " or " BMUs ".BMUs mainly is made up of " osteoclast " " scleroblast " and their cell precursors.In rebuilding circulation, osseous tissue is absorbed by osteoclast on " activation " BNU position, forms to absorb the cavity.Fill this cavity with bone by osteocyte then.
Usually, adult reconstruction circulation is owing to the filling that absorbs the cavity not exclusively causes bone damaged on a small quantity.Therefore, even the loss of dependency bone also can take place to make in year in healthy grownup.But in the osteoporosis case, the quantity of activatory BMUs can increase.The bone reconstruction has been quickened in this activatory increase again, thereby causes unusual high bone loss.
Though the cause of disease of osteoporosis imperfectly understands, there have many Hazard Factor it is believed that to be relevant with osteoporosis.These factors comprise: body weight is light, calcium pickup is few, physical exertion is few and estrogen deficiency.
Treatment to osteoporosis mainly is to use calcium and oestrogenic hormon at present.
Second class relates to the pathological condition that is showed with calcium and phosphoric acid salt abnormal deposition and comprises progressive ossifying myositis, calcinosis universalis and some other illness, makes related tissue the sedimentary pathological condition of calcium occur as sacroiliitis (for example comprising rheumatoid arthritis and osteoarthritis), neuritis, sliding inflammation, tendonitis and other of assisting.
Except osteoporosis, the bone loss also may be caused by rheumatoid arthritis and osteoarthritis.Rheumatoid arthritis is a kind of chronic, systemic and arthrogenous inflammatory diseases.It is unable that its feature is that the joint is assisted with ligament, destroys cartilage, ligament, tendon and bone thereupon.And reduce the viscosity of synovia and other change takes place.Rheumatoid arthritis and symptom comprise general weakness, fatigue, local pain, body joint stiff, unable, swelling and deformity.40 to the sexagenarian women rheumatoid arthritis the most common.
Cause the pathogeny of the rheumatoid arthritis of destruction of joint that two stages are arranged: 1) ooze out the phase, this stage has influence on microcirculation and synovial fluid cell makes plasma proteins and cellular constituent flow to the joint; 2) the chronic inflammatory phase appears under the synovial membrane and under the cartilage, and its feature is to form pannus granulation tissue, bone erosion and cartilage injury in joint cavity.Pannus may form viscosity and scar tissue, causes with the rheumatoid arthritis to be the joint deformity of feature thus.
The cause of disease of rheumatoid arthritis still is unclear.Infectious agent such as bacterium are relevant with it with virus.Present hypothesis thinks that African lymphocytomatosis element (EBV) is the morbid substance that brings out rheumatoid arthritis.
Treatment great majority to rheumatoid arthritis are to alleviate illness by logotype on-steroidal AID at present.The nonsteroidal and-inflammatory drug therapy is mainly effective to early stage rheumatoid arthritis.If the course of disease surpasses 1 year, just can not produce restraining effect to arthritis.People also once attempted adopting gold, methotrexate, and immunosuppressor and reflunomide, but effect is limited.
On the other hand, osteoarthropathy is the non-inflammatory disease of inside, a kind of removable joint.Its feature is the degeneration and the wearing and tearing of joint cartilage, and forms new bone at the articular surface place.Along with the development of osteoarthritis, the surface distress of joint cartilage, a wearing and tearing material obtains to enter the inlet of synovia, and synovia stimulates the phagolysis of scavenger cell conversely.Therefore, finally can bring out Inflammatory response in the osteoarthritis.The general clinical symptom of osteoarthritis comprises: the cartilage of articulations digitorum manus and bone increase, and WA ankylosis, pain on motion.
Treatment to the general symptom of osteoarthritis comprises: anodyne, antiphlogiston, steroid and physiatrics.
Propose various phosphonate derivatives already and can be used for treatment and prevention and calcium and phosphatic abnormal metabolism diseases associated.For example, many reference all disclose and have comprised the particularly two phosphonic acids of polyphosphonic acid such as ethane-1-hydroxyl-1, the composition of 1-di 2 ethylhexyl phosphonic acid (" EHDP "), and they in being suppressed at animal tissues calcium and phosphatic abnormal deposition and move in application, all these documents all are incorporated herein with for referencial use.These documents are US3,683, and 080(1972,8,8 authorize), US4,230,700(1980,10,28 authorize), these two pieces all are issued to Francis, US4, and 868,164(1989,9,19 are issued to Ebetino etc.).Many other class documents disclose the di 2 ethylhexyl phosphonic acid (they are introduced into this paper with for referencial use) that is used for the treatment of osteoporosis and/or arthritic heterocyclic substituted: US4, and 868,164(1989,9,19 are issued to Ebetino etc.); US5,104,863(1992,4,14 are issued to Benedict etc.); US4,267,108(1981,5,12 are issued to Blum etc.); The Ep-A170 of 1986,2,5 open Boehringer Mannhein GmbH, 228; The Ep-A of 1986,7,2 open Benedict and PerKinS, 186,405; US4,754,993(1988,11,15 are issued to Bosies etc.); US4,939,130(1990,7,3 are issued to Jaeggi etc.); US4,971,958(1990,11,20 are issued to Bosies etc.); DE4011777(1990,10,18 is open, Jaeggi.K.) WO90/12017(Dunn, etc., 1990,10,18 is open); WO91/10646(Youssefyeh, R, etc., 1991,7,25 is open); AU-A-26738/88(Jaeggi; 1989,6,15, open); AU-A-45467/89(1990,5,31 is open; Transfer the possession of in Ciba-Geigy) and US4,208,401(1980,6,17 are issued to Bauman).
In addition, the phosphonic acids of sulfur-bearing that also had some document descriptions it is said that they can be used for treating inflammatory symptoms, for example sees: US4, and 746,654(1988,5,24 are issued to Breliere etc., transfer the possession of in Sanofi); US4,876,247) 1989,10,24 are issued to Barbier etc.; EPO100,718 Breliere etc. transfer the possession of in Sanofi 1984,2,15 is open) US 5,071,840(1991,12,10 are issued to Ebetino etc.) di 2 ethylhexyl phosphonic acid that sulfur heterocyclic ring replaces is disclosed, wherein the carbon part of di 2 ethylhexyl phosphonic acid replacement is connected on the nitrogenous six-ring heterocyclic carbon atom.Described compound can be used for treating pathological condition, particularly osteoporosis and the sacroiliitis relevant with phosphatic abnormal metabolism with calcium.
And then, EP298,553(Ebetino, 1989,1,11 is open) and thiol substituting group in other a large amount of substituting groups has been described, they are applicable to the substituting group of doing on the methylene radical phosphine acyl-alkyl phospho acid.But showing the thiol substituting group, the document stronger anti-absorption and arthritis activity are not arranged than many other substituting groups.
Do not have one piece to describe that employing sulphur replaces, nitrogenous heterocyclic diphosphonate (or ester) in these documents yet, phosphonate group carboxylate salt (or ester) and phosphono sulphonyl salt (or ester), prevent and treat osteoporosis and rheumatoid arthritis and osteoarthritis.Ding Yi sulphur substituting group comprises herein: thiol, alkyl sulfhydryl, thioesters, alkyl thioesters, dithioesters and alkyl dithioesters, thiocarbamate, thiocarbamate alkyl ester, dithiocarbamate, dithiocarbamic acid alkyl ester, thiosulfates, thiocarbonic acid SOH alkyl ester, dithiocarbonates and dithiocarbonic acid alkyl ester.And then it is active and have in treatment and it is believed that the activity that added benefit is only arranged for the arthritis prescription mask of inflammatory symptoms that compound of the present invention has the bone protection of joint damaged location in disorder of joint.The term " the bone protection is active " that is used for herein is meant joint damaged location bone and surrounding soft tissue's disease demulcent activity.
Be surprisingly found out that compound of the present invention has stronger fracture assimilating activity than the substituent heterocyclic ring di-phosphonic acid compound of no sulphur, aspect treatment osteoporosis and the sacroiliitis higher treatment validity arranged.
Thereby, an object of the present invention is to provide new more effective compound, it is more effective bone resorption inhibitor aspect osteoporosis treatment, in that it is more effective arthritis agent aspect osteoarthritis and the rheumatoid arthritis treatment, another object of the present invention provides the pharmaceutical composition that is used for the treatment of and prevents calcium and phosphatic abnormal metabolism and be used for the treatment of and prevent sacroiliitis, particularly rheumatoid arthritis and osteoarthritis.In addition, an object of the present invention is to provide with human or other Mammals calcium and phosphatic abnormal metabolism is the treatment of diseases and the prevention method of feature, and these diseases comprise osteoporosis and sacroiliitis, particularly rheumatoid arthritis and osteoarthritis.
These purposes of the present invention and other purpose can more be clear that from the following detailed description of the present invention that provides.
The present invention relates to sulphur replacement, nitrogenous heterocyclic phosphinic acid compounds, comprise diphosphonate (or ester), phosphine acyl-alkyl phosphonate (or ester), phosphono-carboxylic acids salt (or ester) and phosphono sulfonate (or ester), but and their patent medicine salt or ester.And then, the present invention relates to contain the compound of the present invention of safe and effective amount and the pharmaceutical composition of pharmaceutically-acceptable excipients.At last, the invention still further relates to human or other animal calcium and phosphatic abnormal metabolism is the treatment of diseases or the prevention method of feature, comprises treatment or preventing osteoporosis disease and sacroiliitis, particularly rheumatoid arthritis and osteoarthropathy.This method comprise with the The compounds of this invention of safe and effective amount or composition need treat to human or other animals administer.The general structural formula of these compounds is:
Figure 931082773_IMG3
(a) Z is monocyclic or the polycyclic heterocyclic moiety, and it comprises the one or more heteroatomss that are selected among O, S and the N, and wherein has at least one to be N;
(b) Q is a covalent linkage; O, S, N or NR 1;
(c) R is COOH, SO 3H, PO 3H 2Or
P(O) (OH) R 4, R wherein 4For replacing or unsubstituted C 1-C 8Alkyl;
(d) each R 1Be independently selected from :-SR 6;-R 8SR 6; Do not exist; Hydrogen; The C that does not replace or replace 1-C 8Alkyl; The aryl that does not replace or replace; Hydroxyl;-CO 2R 3;-O 2CR 3;-NR 3 2;-OR 3;-C(O) N(R 3) 2;-N(R 3) C(O) R 3; Replace or unsubstituted benzyl; Nitro; Perhaps their mixture;
(e) R 2Be the one or more substituting groups on the atom of Z part, it is independently selected from :-SR 6With-R 8SR 6; R wherein 6Be H;-CO 2R 3;-O 2CR 3;-NR 3 2;-N(R) 3C(O) R 3; Do not exist; Hydrogen; The C that does not replace or replace 1-8Alkyl; The aryl that does not replace or replace; Hydroxyl; Replace or substituted benzyl not; Nitro; Or their mixture;
(f) each R 3Be independently selected from: hydrogen replaces or unsubstituted C 1～C 8Alkyl; Or R 8SR 6;
(g) R 5Be selected from :-SR 6, R 8SR 6, hydrogen; Hydroxyl; Amino; Halogen; The C that does not replace or replace 1～C 8Alkyl; With
(h) R 6Be independently selected from: H;-C(O) R 7; C(S) R 7; C(O) NR 7 2; C(S) NR 7 2; C(O) (OR 7); And C(S) (OR 7); R wherein 7Be hydrogen; Or the C that does not replace or replace 1～C 8Alkyl;
(i) R 8For replacing or unsubstituted C 1-C 8Alkyl; And R 1, R 2, R 3Or R 5In have at least one must be SR 6Or R 8SR 6
In this general formula, Z is nitrogenous, monocycle or many rings, saturated or undersaturated heterocyclic moiety.In addition, m and n and m+n are about integer of 0～about 10 (preferred m+n=0,1 or 2); Q is a covalent linkage or is selected from O, N, S or NR 1Part; R is COOH, SO 3H, PO 3H 2Or P(O) (OH) R 4And then in this general formula, each R 1, R 2, R 3And R 5Be to be independently selected from multiple substituting group, most preferably R 1, R 2, R 3And R 5Be SR 6, R 8SR 6, hydrogen, hydroxyl and amino.R 1, R 2, R 3And R 5In have at least one should be SR 6, or R 8SR 6R 4Be preferably C 1～C 4Alkyl, R 5Be preferably hydrogen, halogen, amino or hydroxyl.R 6Be preferably H, C(O) R 7, C(S) R 7, C(O) NR 7 2, R wherein 7For do not exist, hydrogen or C 1～C 8Alkyl.At last, in this general formula, when Q is S, N, NR 1Or during O, the chain that contains Q can not be connected on the heterocyclic nitrogen-atoms.
As mentioned above, R 1, R 2, R 3And R 5In must have one at least for SR 6Or R 8SR 6; Work as R 1, R 2, R 3Or R 5Any is SR 6Or R 8SR 6The time, heterocycle phosphonate (or ester) is exactly that sulphur replaces.In the compound of the present invention, suitable sulphur substituting group is mercaptan, alkyl sulfhydryl, thioesters, alkylthio ester, dithioesters, dithio alkyl ester, thiocarbamate, thiocarbamate alkyl ester, dithiocarbamate, dithiocarbamic acid alkyl ester, thiocarbonic ester, thiocarbonic acid SOH alkyl ester, dithiocarbonates and dithiocarbonic acid alkyl ester.
The invention still further relates to the compound of the present invention that comprises safe and effective amount and the pharmaceutical composition of pharmaceutically acceptable vehicle.At last, the present invention relates to treat and prevent in the mankind or other Mammals with undesired calcium and phosphoric acid salt metabolism is the pathological conditions of feature.This method comprises human or other Mammals that delivers medicine to the need treatment with the The compounds of this invention of safe and effective amount or composition.
The definition of term and use
The following definition of listing each term used herein.
" heteroatoms " refers to nitrogen, sulphur or Sauerstoffatom.Contain one or more heteroatomic groups and can comprise different heteroatomss.
" alkyl " is meant not replacement or replacement, and straight or branched, saturated or aliphatic unsaturated hydrocarbon, said hydrocarbon chain can be saturated and 1-8 carbon atom arranged that except as otherwise noted, preferably it contains 1-4 carbon atom.Described hydrocarbon chain is unsaturated, and 2-8 carbon atom arranged, and except as otherwise noted, preferably it has 2-4 carbon atom.Correspondingly, term used herein " alkyl " has included the alkene unsaturated chain with at least one olefinic double bond and has had at least one triple-linked alkynes unsaturated chain.Preferred alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl and butyl.
" Heterocyclylalkyl " is meant to have 3-8 atom and comprise carbon atom and one or more heteroatomic saturated chain that does not replace or replace.
" carbocyclic ring " used herein is not replace or replace, saturated, unsaturated or aromatic hydrocarbon ring, and usually, it comprises 3-8 atom, preferred 5-7 atom.Carbocyclic ring can be to contain 3-8, the monocycle of preferred 5-7 carbon atom, perhaps their many rings.Many rings of being made up of ring on two have 6-16 usually, preferably 10-12 carbon atom.Many rings carbocyclic ring of being made up of three rings comprises 13-17 usually, preferred 14-15 atom.
Used in this article " heterocycle " is meant not and replaces or to replace that saturated, unsaturated or aromatic nucleus, this ring comprise 3-8, preferred 5-7 carbon atom and on encircling one or more additional heteroatomss are arranged.Used in this article term " heterocyclic moiety " comprises and condensing or uncondensed, insatiable hunger close, full closing or unsubstituted monocycle or polycyclic system.The monocyclic heterocycles part comprises 3-8 atom usually, preferred 5-7 atom.Many rings heterocyclic moiety of being made up of two rings comprises 6-16 atom usually, preferred 10-12 atom.Many rings heterocyclic moiety of being made up of three rings comprises 13-17 atom usually, preferred 14-15 atom.In addition, encircle heterocyclic moiety more and can form (wherein each ring all contains a nitrogen-atoms) by heterocycle separately, also can form by heterocycle (wherein each ring must contain a nitrogen-atoms) and carbocyclic ring.Each heterocyclic moiety must comprise at least one nitrogen-atoms.Except as otherwise noted, arbitrary additional heteroatoms can be independently selected from nitrogen, sulphur and oxygen in the heterocyclic moiety.
" aryl " is meant that aromatic carbocyclic, preferred aryl groups include but not limited to phenyl, tolyl, xylyl, cumenyl and naphthyl.
" heteroaryl " is meant aromatic heterocycle.Preferred heteroaryl includes but not limited to: thienyl, furyl, pyrryl, pyridyl, pyrazinyl, oxazolyl, thiazolyl, quinolyl, pyrimidyl and tetrazyl.
" alkoxyl group " be one and have the substituent Sauerstoffatom of hydrocarbon chain, wherein hydrocarbon chain be alkyl or alkenyl (as-O-alkyl or-the O-alkenyl).Preferred alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-and alkoxyl group.
" hydroxyalkyl " is meant and has a hydroxyl substituent that (as the hydrocarbon chain of-OH) replacement, it also can have other substituting group.Preferred hydroxyalkyl includes but not limited to hydroxyethyl, hydroxypropyl and hydroxyalkyl.
" carboxyalkyl " is meant and has a carboxyl substituent that (as the hydrocarbon chain of-COOH) replacement, it also can have other substituting group.Preferred carboxyalkyl includes but not limited to carboxymethyl, propyloic and their acid and ester.
" aminoalkyl " is meant with an amine moiety (hydrocarbon chain (as alkyl) that replaces as alkyl-NH-), for example methylamine.
" alkylamino " is meant amino part with one or two alkyl substituent (as-N-alkyl), for example dimethyl amine.
" alkenyl amino " is meant amino part with one or two alkenyl substitutents (as-N-alkenyl).
" alkynyl amino " is meant amino part with one or two alkynyl substituted base (as-N-alkynyl).
" alkane imino-" be meant imino-part with one or two alkyl substituent (as-N-alkyl-).
" aralkyl " is meant the moieties that replaces with aryl.Preferred aralkyl comprises benzyl and styroyl.
" virtue amino " is meant the amino part that replaces with aryl (as-NH-aryl).
" aryloxy " is meant Sauerstoffatom with aryl substituent (as-O-aryl).
" acyl group " or " carbonyl " be meant two keys (as R-C(=O) of carbon and oxygen-).Preferred alkyl acyl includes but not limited to ethanoyl, propionyl, butyryl radicals and benzoyl.
" acyloxy " is meant Sauerstoffatom with acyl substituent (as-O-acyl group); For example ,-O-C(=O)-alkyl.
" amido " is meant amino part with acyl substituent (as-N-acyl group); For example ,-NH-(C=O)-alkyl.
" halogen ", " halogen " or " halogenide " is meant the former subbase of chlorine, bromine, fluorine or iodine.Preferred chlorine, bromine and fluorine.
Being referred to herein as " rudimentary " hydrocarbon part (as " rudimentary " alkyl) is meant and unless otherwise indicated comprises 1-6, the hydrocarbon chain of preferred 1-4 carbon atom.
Term used herein " sulfo--substituting group " is by SR 6Or R 8SR 6Described, R wherein 8Be C 1～C 8Alkyl.Concrete sulfo--substituting group comprises: thiol (SH, wherein R 6=H); Thioesters (
Figure 931082773_IMG4
, R wherein 6Be COR 7); Thiocarbamate (
Figure 931082773_IMG5
, R wherein 6Be CONR 7); Dithiocarbamate ( , R wherein 6Be CSNR 7 2); Dithioesters ( , R wherein 6Be CSR 7); Thiocarbonic ester
(
Figure 931082773_IMG8
, R wherein 6Be C(O) OR 7); And dithiocarbonates (
Figure 931082773_IMG9
, R wherein 6Be C(S) OR 7).Here used R 7Be hydrogen or replacement or unsubstituted C 1～C 8Alkyl.Be appreciated that.R 8(as C 1～C 8Alkyl) can place SR as defined above 6The group front; This will form the alkyl thiol; Alkylthio ester, dithio alkyl ester, thiocarbamate alkyl ester, dithiocarbamic acid alkyl ester, thiocarbonic acid SOH alkyl ester and dithiocarbonic acid alkyl ester.
Used in this article term " diphosphonate (or ester) " or " two phosphonic acids " are meant to have those phosphonates (or ester) or the phosphonic acids that is connected in two phosphonyl groups on the same carbon atom, and they can be replaced with term diphosphonate (or ester) and di 2 ethylhexyl phosphonic acid and use.Use structure described here, R partly is PO in these compounds 3H 2
" but patent medicine salt " is meant the cationic salts that forms with any acidity (as carboxyl) group, perhaps the anion salt that forms with any alkalescence (as amino) group.In the prior art, many these class salt all are known, as people such as Johnston, 1987,9,11 disclosed world patents disclose 87/05297 described those, it is for reference here that the document is introduced.Preferred cation salt comprises an alkali metal salt (as sodium salt and sylvite), alkaline earth salt (as magnesium salts and calcium salt), and preferred anionic surfactants salt comprises halogenide (as muriate), acetate and carbonate.
" but the ester of biological hydrolysis " is meant that phosphinic acid compounds that sulphur replaces can not influence the activity of compound, perhaps is easy to by human or other Mammals metabolism to produce active compound.Many these esters all are known in the prior art, as people such as Johnston 1987,9,11 disclosed world patents disclose 87/05297 described those, the document is introduced here with for referencial use.This kind ester comprises: lower alkyl esters; Low-grade acyloxy alkyl ester (as acetyl-o-methyl ester, acetyl oxygen ethyl ester, amino carbonyl oxy-methyl ester, oxy acid methyl neopentyl ester and new pentane acyloxy ethyl ester); Lactone (as 2-benzo [C] furanonyl ester and sulfo-2-benzo [C] furanonyl ester); Lower alkoxy acyloxy alkyl ester (as methoxy carbonyl oxy-methyl ester, ethoxy carbonyl oxygen base ethyl ester and the different third oxygen carbonyl oxygen base ethyl ester); Alkoxy alkyl, cholinesterase and amidoalkyl ester (as the acetylamino methyl ester).
As above the definition and here employed substituting group self also can be substituted.The available one or more substituting groups of this replacement replace.These substituting groups include but not limited to the Biology(1979 at the Substituent of C.HanSch and A.Leo Constants for correlation Analysis in Chemistry and) listed those; the document is introduced here with for referencial use; preferred substituted includes, but are not limited to alkyl; alkenyl; alkoxyl group; hydroxyl; oxo; amino; aminoalkyl (as aminomethyl etc.); cyano group; halogen; carboxyl; alkoxyl group ethanoyl (as ethoxycarbonyl etc.), sulphur; thiol; aryl; cycloalkyl; heteroaryl; Heterocyclylalkyl (as: piperidyl; morpholinyl; piperazinyl; pyrrolidyl etc.).Imino-, sulfo-, hydroxyalkyl, aryloxy, aralkyl and its mixture.
The nitrogenous heterocyclic phosphinic acid compounds of sulfo-
Compound of the present invention is heterocyclic phosphonic acids and Qi Ke patent medicine salt or the ester that sulphur replaces, and wherein contains the phosphonic carbon atom and is connected on the nitrogen heterocyclic ring carbon atom partly, on the carbon atom of preferred pyridine ring part.Contain phosphonic carbon atom and heterocyclic moiety and can directly pass through covalent linkage (preferred singly-bound) bonding, perhaps pass through the long-chain bonding of about 1～about 10 atoms.If above-mentioned bonding realizes that by connection chain this chain can be a carbon atom entirely, Sauerstoffatom of a nitrogen-atoms or nitrogenous chain or contain oxygen chain, sulphur atom or sulfur-bearing chain.Carbon atom on the connection chain and nitrogen-atoms can be substituted or be substituted by one or more substituting groups independently, and said substituting group is selected from the sulphur substituting group and (comprises: mercaptan, alkyl sulfhydryl, thioesters, alkylthio ester, dithioesters, dithio alkyl ester, thiocarbamate, thiocarbamate alkyl ester, dithiocarbamate, dithiocarbamic acid alkyl ester, thiocarbonic ester, thiocarbonic acid SOH alkyl ester, dithiocarbonates and dithiocarbonic acid alkyl ester, hydrogen, hydroxyl, methyl, ethyl or propyl group.Carbon on the described chain or nitrogen-atoms can not be substituted yet.Also preferred this chain length is an atom, as-CH 2-,-NH-and-O-.
For the compound that the nitrogen on the connection chain, sulphur or Sauerstoffatom are bonded to heterocyclic moiety, this nitrogen, sulphur or Sauerstoffatom be bonded on the carbon atom of ring and Direct Bonding to the nitrogen-atoms of ring.The present invention has also comprised more such compounds, in this compound, nitrogen-atoms on the connection chain is bonded on the heterocycle, and this nitrogen-atoms is bonded on the carbon atom of a Direct Bonding to the heterocyclic nitrogen atom, thereby these compounds have a fork structure (as described in more detail below).When Q was N, S, O, NR ' and m=0, Q was preferably bound on the carbon atom of ring.When Q was covalent linkage, connection chain can be bonded on the carbon atom of ring or on the nitrogen-atoms.
The carbon atom that links to each other with phosphonyl group is unsubstituted (as a hydrogen atom) or replacement.This carbon atom can replace (double phosphinic acid compounds is provided) with two phosphonyl groups; Perhaps replace (producing the phosphine acyl-alkyl phosphonous compound) with a phosphonyl group and a phosphonous acid group; Replace (producing the phosphono sulfoacid compound) with a phosphonyl group and a sulfonic acid group; Or replace (producing the phosphono-carboxylic acids compound) with a phosphonyl group and hydroxy-acid group.
And then the carbon atom on the heterocycle can be unsubstituted or replace with one or more substituting groups independently that the nitrogen-atoms on the heterocycle also can be unsubstituted or replace.
Compound of the present invention must have at least one sulphur substituting group such as SR 6Or R 8SR 6Part is necessary.Correspondingly, R 1, R 2, R 3Or R 5In have at least one to be necessary for SR 6Or R 8SR 6
Therefore, sulphur replacement of the present invention, nitrogenous heterocyclic phosphonic acids and Qi Ke patent medicine salt or ester have following general formula:
Figure 931082773_IMG10
Wherein m and n are 0～10 integer, and m+n equals 0～10.
(a) Z is monocycle or encircles heterocyclic moiety more, and it comprises the heteroatoms of one or more O of being selected from, S or N, and one of them is N at least;
(b) Q is covalent linkage, O, N, S or NR 1;
(c) R is COOH, SO 3H, PO 3H 2Or P(O) (OH) R 4; R wherein 4Be C 1～C 8Alkyl;
(d) each R 1Be independently selected from-SR 6;-R 8SR 6; Do not have; Hydrogen; The C that does not replace or replace 1～C 8Alkyl; The aryl that does not replace or replace; Hydroxyl;-CO 2R 3;-O 2CR 3;-NR 3 2;
-N（R 3）C（O）R 3;-OR 3;
-C(O) N(R 3) 2; Replace or unsubstituted benzyl; Nitro, or their mixture;
(e) R 2Be the substituting group on the Z part of atoms, can be independently selected from :-SR 6;-R 8SR 6;-CO 2R 3;-O 2CR 3;-NR 3 2;-N(R) 3C(O) R 3; OR 3;-C(O) N(R 3) 2; Do not have; Hydrogen; The C that does not replace or replace 1～C 8Alkyl; The aryl that does not replace or replace; Hydroxyl; Replace or unsubstituted benzyl; Nitro; Or their mixture;
(f) each R 3Be independently selected from: hydrogen; Replace or unsubstituted C 1～C 8Alkyl; Or R 8SR 6;
(g) R 5Be selected from :-SR 6; R 8SR 6; Hydrogen; Hydroxyl; The C that does not replace or replace 1～C 8Alkyl; Amino; Halogen; With
(h) R 6Be H;-C(O) R 7;-C(S) R 7 2;-C(O) NR 7 2;-C(S) NR 7; C(O) OR 7; Or C(S) OR 7, R wherein 7For hydrogen or the C that does not replace or replace 1～C 8Alkyl;
(i) R 8Be C 1～C 8Replace or unsubstituted alkyl; And R 1, R 2, R 3Or R 5In have one at least for SR 6Or R 3SR 6
In the general formula, Z is the nitrogen heterocyclic ring part.Said heterocyclic moiety can be monocycle system (as a heterocycle), also can be polycyclic system (as a heterocycle and one or more heterocycle or carbocyclic ring).Each Z part should comprise a nitrogen heteroatom at least and can comprise one or more additional heteroatomss that are selected from oxygen, sulphur or nitrogen.
In the general formula, Q is a covalent linkage (being preferably a singly-bound), perhaps for be selected from oxygen, sulphur, nitrogen or-NR 1Part.And then m and n and m+n are the integer of about 0-about 10, preferred m+n=0 or 1; For Q be oxygen or-NR 1The time more preferably m=0 and n=0 or 1; For Q is the situation of covalent linkage, preferred m+n=0,1 or 2.
R part as herein described can be COOH, SO 3H, PO 3H 2Or P(O) (OH) R 4, R wherein 4Be C 1～C 8Alkyl.When R is PO 3H 2The time, the phosphinic acid compounds that sulphur replaces is diphosphonate (or ester); When R is P(O) (OH) R 4The time, the phosphinic acid compounds that sulphur replaces is phosphonoalkyl phosphinate (or ester); When R is SO 3During H, the phosphinic acid compounds that sulphur replaces is phosphono sulfonate (or ester); When R was COOH, the phosphinic acid compounds that sulphur replaces was phosphono-carboxylic acids salt (or ester).
As mentioned above, R 1, R 2, R 3Or R 5In have one at least for SR 6Or R 8SR 6Be necessary; At R 1, R 2, R 3Or R 5In any is SR 6Or R 8SR 6The time, heterocycle phosphonate (or ester) is that sulphur replaces.The suitable sulphur substituting group of The compounds of this invention comprises: mercaptan, alkyl sulfhydryl, thioesters, alkylthio ester, dithioesters, dithio alkyl ester, thiocarbamate, thiocarbamate alkyl ester, dithiocarbamate, dithiocarbamic acid alkyl ester, thiocarbonic ester, thiocarbonic acid SOH alkyl ester, dithiocarbonates and dithiocarbonic acid alkyl ester.
R 1Part is a substituting group, and is independently selected from: thiol, alkyl thiol, thioesters, alkylthio ester, dithioesters, dithio alkyl ester, thiocarbamate, thiocarbamate alkyl ester, dithiocarbamate, dithiocarbamic acid alkyl ester, thiocarbonic ester, thiocarbonic acid SOH alkyl ester, dithiocarbonates, dithiocarbonic acid alkyl ester, hydrogen, halogen, C 1-C 8Alkyl, the aryl that does not replace or replace, the benzyl that does not replace or replace; Hydroxyl;-C(O) N(R 3) 2;-OR 3;-CO 2R 3;-O 2CR 3; NR 3 2;-N(R 3) C(O) R 3; Nitro; With their mixture; R wherein 3Be independently selected from R 8SR 6, hydrogen, replacement or unsubstituted C 1-C 8Alkyl, the alkyl that preferred sulphur replaces.When Q is covalent linkage and arbitrary R 1When not existing, adjacent R 1Do not exist yet; This shows a kind of unsaturated chain; When Q is NR 1, R 1Not existing between expression carbon nitrogen is two keys.
But when n=O and Q are oxygen, sulphur or nitrogen, R 5Be selected from: the alkyl of hydrogen, about 1～about 8 carbon atoms; R 8SR 6But, its patent medicine salt and ester; And their mixture.
Preferred R 1Be selected from: sulphur substituting group, hydrogen, chlorine, methyl, ethyl, hydroxyl, unsubstituted amino, (N-methyl) are amino, (N, N-dimethyl) is amino ,-CO 2H and Qi Ke patent medicine salt ,-CO 2CH 3With-CONH 2R more preferably 1Be selected from: thiol, (or sulfur-bearing substituting group), hydrogen, methyl, chlorine, amino and hydroxyl.R more preferably 1Be thiol, hydrogen, hydroxyl or amino.In addition, as mentioned above, in the compound of the present invention, R 1, R 2, R 3And R 5In have one at least for sulfur-bearing substituting group such as SR 6Or R 8SR 6Be necessary.
The heterocyclic moiety of The compounds of this invention can be unsubstituted, or with one or more substituting group (R 2) on the atom of ring, replace independently.R 2Group can be on the same carbon atom of heterocyclic moiety or on different atoms.
Therefore, R 2Be the substituting group on the one or more atoms of heterocyclic, R 2Can be independently selected from: do not exist; SR 6, R 8SR 6; Hydrogen, halogen; C 1～C 8Alkyl; The aryl that does not replace or replace; The benzyl that does not replace or replace ,-C(O) N(R 3) 2;-OR 3;-CO 2R 3;-O 2CR 3;-NR 3 2;-N(R 3) C(O) R 3; Nitro, and their mixture, wherein R 3Be independently selected from: hydrogen, the C that does not replace or replace 1～C 8Alkyl, the alkyl that preferred sulphur replaces.
R preferably 2Substituting group is independently selected from: the sulphur substituting group; (SR 6, R 8SR 6), hydrogen, methyl, ethyl, hydroxyl, unsubstituted amino, (N-methyl) amino, (N, N-dimethyl) amino, chlorine, methoxyl group, oxyethyl group, nitro ,-CO 2H and Qi Ke patent medicine salt ,-CO 2CH 3, CONH 2And their mixture.R more preferably 2Substituting group is independently selected from: the sulfur-bearing substituting group; Hydrogen, methyl, amino, chlorine, methoxyl group, hydroxyl and their mixture.R most preferably 2Substituting group is independently selected from: the sulfur-bearing substituting group; Hydrogen and methyl.In addition, as mentioned above, in the compound of the present invention, R 1, R 2, R 3And R 5In have one at least for sulfur-bearing substituting group such as SR 6Or R 8SR 6Be necessary.
The as above R in the general formula 5Be meant hydrogen, halogen, hydroxyl, amino, sulphur substituting group such as SR 6Or R 8SR 6, the C that do not replace or replace 1～C 8Alkyl.R 5Preferred hydroxyl, amino, hydrogen, halogen, sulphur; R 5Be preferably hydroxyl, amino and hydrogen.
R 6Be meant sulfur-bearing substituting group-SR 6On a substituting group.R 6Be hydrogen;-C(O) R 7;-C(S) R 7;-C(O) NR 7 2;-C(S) NR 7 2;-C(O) OR 7;-C(S) OR 7, R wherein 7Can there be hydrogen, the C that does not replace or replace 1～C 8Alkyl.Preferred R 6Be H, C(O) R 7, C(O) NR 7; R 6Be preferably hydrogen.Preferred R 7Be hydrogen or C 1～C 8Alkyl.
Z of the present invention partly is the nitrogen heterocyclic ring part.Said heterocyclic moiety contains the one or more heteroatomss that are selected among O, S or the N, wherein has at least one to be nitrogen-atoms.The Z part can be monocyclic heterocycles part with 3～8 atoms or the many rings heterocyclic moiety with 6～17 atoms.Said many loop sections can comprise two or more heterocycles, perhaps a heterocycle and one or more carbocyclic ring; But must have at least one nitrogen-atoms by at least one heterocycle in the heterocyclic moiety; Thereby heterocyclic moiety comprises a nitrogen heterocyclic ring at least.
Preferred monocycle Z partly is pyrimidine, pyrazine, piperidines and pyridine.
Preferred many ring Z part quinoline, pyrrolopyridine, quinoxaline and imidazopyridine.
And then in aforementioned formula, when m=0 and Q are oxygen or nitrogen, then Q part and the best following restriction of heterocyclic bonding.Q partly is bonded on the heterocyclic carbon atom and Direct Bonding (as 3,4 or 5 of piperidine ring when being 1 counting with the nitrogen-atoms on the ring) to the heterocyclic nitrogen atom not, unless when Q is nitrogen, Q also can be incorporated on the heterocycle by pitching structural bond.
Compound of the present invention with fork structure comprises the N=C-N chemical bond as heterocyclic moiety.
The preferred sulphur of the present invention replaces, and the double phosphinic acid compounds that contains pyridine has following universal architecture formula.
Figure 931082773_IMG11
Connection chain has heteroatoms such as Q=S, O, N or NR 1The sulphur diphosphonate (or ester) that replaces, contain pyridine also be preferred.
Figure 931082773_IMG12
Figure 931082773_IMG13
In addition, two phosphonic acids of the piperidines of sulphur replacement of the present invention and Qi Ke patent medicine salt and ester can be following another kind of universal architecture formula:
Figure 931082773_IMG14
The double phosphinic acid compounds that other sulphur replaces comprises the partly compound for encircling many rings heterocyclic moiety of forming by two of those Z.
Figure 931082773_IMG15
Two phosphonic acids that other preferred sulfur heterocyclic ring replaces are that Z partly is those compounds of pyrimidine.The universal architecture formula of these compounds and Qi Ke patent medicine salt or ester is as follows:
Figure 931082773_IMG16
The heterocyclic ring di-phosphonic acid that other suitable sulphur replaces comprises that Z is those compounds of seven member heterocyclic ring containing nitrogens.Its universal architecture formula is as follows:
Figure 931082773_IMG17
Z also is preferred for the two phosphonic acids of the sulphur substituted heterocycle of five-membered ring partly, and its universal architecture formula is as follows:
Figure 931082773_IMG18
Figure 931082773_IMG19
R wherein 2Be selected from hydrogen or methyl, R 2Preferred hydrogen; R 3And R 4For being independently selected from the substituting group of hydrogen, methyl, amino, chlorine, methoxyl group, hydroxyl and their mixture, R 3And R 4Be preferably hydrogen or methyl.
The specific examples of The compounds of this invention comprises:
[(the 5-[mercapto methyl]-the 2-piperidyl) methylene radical] two [phosphonic acids];
[(5-mercapto methyl-3-piperidyl) methylene radical] two [phosphonic acids];
[(5-sulfydryl-2-piperidyl) methylene radical] two [phosphonic acids];
[(5-[4-sulfydryl butyl]-the 2-piperidyl) methylene radical] two [phosphonic acids];
[(5-sulfydryl-3-piperidyl) methylene radical] two [phosphonic acids];
[(5-[5-sulfydryl amyl group]-the 3-piperidyl) methylene radical] two [phosphonic acids];
[(the 5-[2-mercaptoethyl]-the 4-piperidyl) methylene radical] two [phosphonic acids];
[(5-sulfydryl-4-piperidyl) methylene radical] two [phosphonic acids];
[2-(5-sulfydryl-2-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-[3-sulfydryl propyl group]-2-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-sulfydryl-3-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-sulfydryl-4-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-[4-sulfydryl butyl]-2-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-mercapto methyl-3-piperidyl) ethylidene] two [phosphonic acids];
[2-(5-sulfydryl-2-piperidyl]-1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-(3-sulfydryl propyl group)-2-piperidyl]-1-hydroxyl] ethylidene] two [phosphonic acids];
[(2-[5-sulfydryl-3-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-(2-mercaptoethyl)-3-piperidyl]-1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-sulfydryl-4-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-mercapto methyl-4-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-mercapto methyl-3-methyl-2-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[5-sulfydryl-3-methyl-2-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[3-mercapto methyl-5-methyl-2-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[2-[5-mercapto methyl-3-methyl-2-piperidyl] ethylidene] two [phosphonic acids];
[2-(3-mercapto methyl-5-methyl-2-piperidyl) ethylidene] two [phosphonic acids];
[the 3-[5-(mercapto methyl)-the 2-piperidyl] propylidene] two [phosphonic acids];
[the 3-[5-(mercapto methyl)-the 3-piperidyl] propylidene] two [phosphonic acids];
[the 3-[5-(mercapto methyl)-the 4-piperidyl] propylidene] two [phosphonic acids];
[the 3-[5-(mercapto methyl)-the 2-piperidyl]-1-hydroxyl-propylidene] two [phosphonic acids];
[3-[5-sulfydryl-3-piperidyl]-1-hydroxy propylidene] two [phosphonic acids];
[3-[5-(4-sulfydryl butyl)-the 4-piperidyl]-the 1-hydroxy propylidene] two [phosphonic acids];
[2-(3-mercapto methyl-5-methyl-2-pyridyl) ethylidene] two [phosphonic acids];
[2-(5-[3-sulfydryl propyl group]-2-methyl-2-piperidyl) ethylidene] two [phosphonic acids];
[(2-[5-(2-sulfydryl propyl group)-2-piperidyl]-1-amino) ethylidene] two [phosphonic acids];
[(2-[5-(3-sulfydryl propyl group)-3-piperidyl]-1-amino) ethylidene] two [phosphonic acids];
[2-(5-[3-sulfydryl propyl group]-4-piperidyl)-the amino ethylidene of 1-] two [phosphonic acids];
[2-[3-methyl-5-(3-sulfydryl propyl group)-the 2-piperidyl]-the 1-hydroxyl) ethylidene] two [phosphonic acids];
[(2-[3-amino-5-(3-sulfydryl propyl group)-2-piperidyl]-1-hydroxyl) ethylidene] two [phosphonic acids];
[2-[5-sulfydryl-2-(1,4-diazine) ethylidene] two [phosphonic acids];
[2-[5-(3-sulfydryl propyl group)-2-(1, the 4-diazine) ethylidene] two [phosphonic acids];
[2-[5-(3-sulfydryl propyl group)-2-(1, the 4-diazine)]-the 1-hydroxy ethylene] two [phosphonic acids];
[2-[5-sulfydryl-2-(1,4-diazine]-1-hydroxy ethylene] two [phosphonic acids];
[2-[5-sulfydryl-2-(1,3-diazine)] ethylidene] two [phosphonic acids];
[2-[5-(3-sulfydryl propyl group)-2-(1, the 3-diazine)] ethylidene] two [phosphonic acids];
[2-[5-(3-sulfydryl propyl group)-2-(1, the 3-diazine)]-the 1-hydroxy ethylene] two [phosphonic acids];
[2-[5-sulfydryl-2-(1,3-diazine]-1-hydroxy ethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-the 2-piperidyl) aminomethylene] two [phosphonic acids];
[(5-sulfydryl-2-piperidyl) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-the 3-piperidyl) aminomethylene] two [phosphonic acids];
[(5-sulfydryl-3-piperidyl) aminomethylene] two [phosphonic acids];
[(5-sulfydryl-4-piperidyl) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-the 4-piperidyl) aminomethylene] two [phosphonic acids];
[(5-sulfydryl-3-methyl-2-piperidylidene) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-3-methyl-2-piperidylidene) aminomethylene] two [phosphonic acids];
[2-(5-sulfydryl-3-methyl-2-piperidylidene) amino ethylidene] two [phosphonic acids];
[2-(5-[3-sulfydryl propyl group]-3-methyl-2-piperidylidene) aminomethylene] two [phosphonic acids];
[(5-sulfydryl-2-piperidylidene) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-the 2-piperidylidene) aminomethylene] two [phosphonic acids];
[2-(5-sulfydryl-2-piperidylidene) amino ethylidene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-the 2-piperidylidene) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-2-(1, the inferior diazine of 4-) aminomethylene] two [phosphonic acids];
[(5-[3-sulfydryl propyl group]-2-[1, the inferior diazine of 3-) aminomethylene] two [phosphonic acids];
[(4-[3-sulfydryl propyl group]-2-[1,3, the inferior triazinyl of 5-) aminomethylene] two [phosphonic acids];
N-(2 '-(1 ', 3 '-the Ya diazine)-the aminomethane di 2 ethylhexyl phosphonic acid; But with their patent medicine salt and ester.
In order to measure and estimate pharmaceutical activity, adopt various testing method known to a person of ordinary skill in the art, carried out the test of di 2 ethylhexyl phosphonic acid compound in animal body.Therefore, use and a kind ofly suppress the method that bone resorption abilities set and just can represent the anti-assimilating activity of body endoskeleton expediently, said bone resorption performance characterization calcium and phosphatic abnormal metabolism by testing these compounds.The example of such known test comprises SchenK model mouse models and the test of auxiliary sacroiliitis.Hydroxyapatite crystal production inhibition test also is useful in the glass test tube pipe.These tests and other pharmaceutical activity evaluation test are all open and/or referring to following document: Shinoda, etc., Calcified Tissue International 35, p87-99(1983); Schenk etc., Calcified Tissue Research, 11, p196-214(1973); Calcified Tissue Research such as Russell, 6 p183-196(1970); Muhibauer and Fleisch, Mineral Electrolyte Metab, 5, P296-303(1981); People such as MancolLas, Oral Biol, 15,731(1970); US patent 3,683,080(Francis, 1972.8.8 authorizes); US patent 4,134,969(Schmidt-Dunker, 1979.1.16 authorizes); EPO-A-189,662(1986.8.6 is open); All these documents are intactly introduced the present invention with for referencial use.In the following embodiment that provides, describe some pharmaceutical activity tests wherein in detail.
Except can be used as calcium or phosphatic abnormal metabolism be feature pathological situation treatment or the prevention, compound of the present invention also has other some purposes.For example, compound of the present invention it is believed that with can be used as the bone scanning agent behind the 99m-mtc labeled.In addition, compound of the present invention also can be used as the particularly sequestering agent of divalence (as calcium and magnesium) and trivalent metal ion (as indium) of polyvalent metal ion.Auxiliary agent when therefore, compound of the present invention can be used as washing composition and sanitising agent auxiliary agent or treating water.They also can be used as the stablizer of compound.In addition, they also can be used for preventing the formation of winestone on the tooth (as calculus) and/or plaque.At last, compound of the present invention is useful as herbicides also, and it is nontoxic to animal.
The method preparation that the phosphinic acid compounds of sulphur substituted nitrogen-containing heterocyclic of the present invention can adopt embodiment A-H herein to provide.
Comprise new sulphur replacement, the composition of nitrogenous heterocyclic phosphinic acid compounds
New phosphinic acid compounds of the present invention can be by all means to human or other animals administer, and these modes include but not limited to: oral and injection (intravenously, intramuscular, intraperitoneal and subcutaneous injection).Those of ordinary skill in the art adopts the appropriate drug vehicle that limits below can make many other form of medication that novel sulphur of the present invention replaces phosphinic acid compounds that comprise at an easy rate.Consider from the angle that the patient is easy to accept, usually the mode of best employing oral administration.
Term used herein " pharmaceutical composition " is meant that the sulphur that comprises safe and effective amount replaces the activeconstituents of phosphinic acid compounds or the mixture of its mixture and pharmaceutically-acceptable excipients.
The consumption that term used herein " safe and effective amount " is meant compound and composition the medical judgment scope planted agent of safety enough greatly improving the symptom and/or the illness of desire treatment significantly, but enough little to avoid producing severe side effect (reasonably benefit/risk compares).The safe and effective consumption of the used activeconstituents of employed pharmaceutical composition can change because of various factors in the method for being invented in this article, these factors comprise the concrete illness that will treat, patient's age and physical appearance, the severity of disease, the time length of treatment, coefficient other therapeutic modality, the concrete activeconstituents that is adopted, the other factors in concrete pharmaceutically-acceptable excipients that is adopted and doctor in charge's the knowledge and experience scope.
Term used herein " pharmaceutically-acceptable excipients comprises any biologically inert known to a person of ordinary skill in the art, the inactive material of medicine, and it should be compatible with the physics and the chemical property of selected concrete phosphinic acid compounds activeconstituents.Pharmaceutically-acceptable excipients includes but not limited to: polymkeric substance, resin, softening agent, weighting agent, tackiness agent, lubricant, antiseize paste (glidant) decomposition agent, solvent, cosolvent, buffer system, tensio-active agent, sanitas, sweeting agent, flavouring agent, pharmaceutical grade dyestuff or pigment and sticky agent.
Term used herein " oral administration form " is meant in patient's gastrointestinal system is delivered to said composition in the patient oral cavity and any required pharmaceutical composition is systematically delivered medicine to the patient with regard to situation of the present invention, the form of taking can be the dressing or the tablet of dressing not, solution, suspension; Perhaps dressing or the not capsule of dressing.
Term used herein " injection " be meant by carrying the solution that contains activeconstituents or emulsion through patient skin is had an injection so that said solution or emulsion through intravenously, intramuscular, intraperitoneal and subcutaneous injection are delivered in patient's the recycle system and make any required pharmaceutical composition systematically deliver medicine to people or other Mammals.
Those of ordinary skill in the art can adopt following one or more modes with the transmission speed of Controlling System satisfactorily:
(a) activeconstituents performance;
(b) pharmaceutically-acceptable excipients; As long as change the activity of not disturbing selected concrete active ingredient;
(c) denseness of the desired said vehicle that has of the type of vehicle and accompaniment and perviousness (expansion character);
(d) the temporal dependence condition in vehicle self and/or the vehicle;
(e) particle size of granulous active ingredient; With
(f) pH value of vehicle is comply with condition.
Particularly, the factor of selecting to instruct as performance can be that different sulphur replace phosphonate (or ester) activeconstituents solubleness, acid and hydrolysis susceptibility, and said activeconstituents for example is an acid salt, promptly with the salt such as an alkali metal salt of OH-form, alkaline earth salt etc.; And ester, as alkyl, alkenyl, aryl, the ester of aralkyl.In addition, make oral preparation reach suitable PH condition by in activeconstituents, adding suitable buffer reagent with consistent with desirable release profile.
As mentioned above, pharmaceutically-acceptable excipients includes but not limited to: resin, weighting agent, binding property, lubricant, solvent, antiseize paste, decomposition agent, cosolvent, tensio-active agent, sanitas, sweeting agent, flavouring agent, buffer system, pharmaceutical grade dyestuff or pigment and sticky agent.
Preferred solvent is a water.
Flavouring agent used herein comprises following document those disclosed: Remington ' s Pharmaceutical Sciences the 18th edition, and MacK Publishing Company, 1990 1288-1300 pages or leaves, the document is introduced for reference here.The pharmaceutical composition of Shi Yonging comprises the flavouring agent of 0-2% usually herein.
Dyestuff used herein or pigment comprise following document those disclosed: HandbooK of Pharmaceutical Excipients 81-90 page or leaf, 1986, American Pharmaceutical Association ﹠amp; The The Pharmaceutical Society of Great Britain document is introduced for reference here, and the pharmaceutical composition here contains 0-2% dyestuff or pigment usually.
Preferred cosolvent includes, but are not limited to ethanol, glycerine, propylene glycol, polyoxyethylene glycol.Pharmaceutical composition of the present invention comprises the cosolvent of 0-5%.
Preferred buffer system includes but not limited to acetate, boric acid, carbonic acid, phosphoric acid, succsinic acid, toxilic acid, tartrate, citric acid, acetate, phenylformic acid, lactic acid, R-Glyceric acid, glyconic acid, pentanedioic acid, L-glutamic acid and their sodium, potassium and ammonium salt.Particularly preferably be phosphoric acid, tartrate, citric acid and acetate and their salt.Usually the buffer system that contains 0-5% in the pharmaceutical composition of the present invention.
Preferred surfactants but be not limited to: Vykamol Sorbitol 8B, polyoxyethylene monoalkyl ethers, sucrose monoester and lanolin ester and ether, alkyl-sulphate, the sodium of lipid acid, potassium and ammonium salt.Pharmaceutical composition of the present invention comprises the tensio-active agent of 0-2%.
Preferred sanitas includes but not limited to: phenol, alkyl paraben, orthoxenol phenylformic acid and its salt, boric acid and its salt, Sorbic Acid and its salt, chlorobutanol, benzylalcohol, thiomersal(ate), acetate and Phenylmercurinitrate, nitrophenol mercury, benzalkonium chloride, pyrisept, para methyl paraben, propylparaben.Composition of the present invention contains the sanitas of 0-2% usually.
Preferred sweeteners includes but not limited to: sucrose, glucose, asccharin, Sorbitol Powder, mannitol and aspartame.Particularly preferably be sucrose and asccharin.Pharmaceutical composition of the present invention comprises the sweeting agent of 0-5%.
Preferred sticky agent includes but not limited to: methylcellulose gum, Xylo-Mucine, Vltra tears, hydroxypropylcellulose, sodium alginate, carbomer, Povidone, gum arabic, pawl ear natural gum, xanthan gum and tragacanth gum.Particularly preferably be methylcellulose gum, carbomer, xanthan gum, pawl ear natural gum, Povidone, Xylo-Mucine and silicoaluminate magnesium.Composition of the present invention comprises the sticky agent of 0-5%.
Preferred weighting agent includes but not limited to: lactose, N.F,USP MANNITOL, Sorbitol Powder, ternary calcium phosphate, secondary calcium phosphate, compression sugars, starch, calcium sulfate, the Mierocrystalline cellulose of dextrorotation and crystallite.Composition of the present invention comprises the weighting agent of 0-75%.
Preferred lubricant includes but not limited to: Magnesium Stearate, stearic acid and talcum.Pharmaceutical composition of the present invention comprises the lubricant of 0.5-2%.
Preferred antiseize paste includes but not limited to talcum and colloid silica.Composition of the present invention comprises the antiseize paste of 1-5%.
Preferred decomposition agent includes but not limited to: starch, sodium starch glycollate, Crospovidone, Croscarmelose Sodium and Microcrystalline Cellulose.Pharmaceutical composition of the present invention comprises the decomposition agent of 4-15%.
Preferred adhesive includes but not limited to: gum arabic, tragacanth gum, hydroxypropylcellulose, pregelatinized starch, gelatin, Povidone, hydroxypropylcellulose, Vltra tears, methylcellulose gum, sugar soln such as sucrose and Sorbitol Solution USP, ethyl cellulose.Composition of the present invention comprises the tackiness agent of 1-10%.
Compound of the present invention can account for about 0.1%-about 99% of pharmaceutical composition weight of the present invention.Compound preferably of the present invention accounts for about 15%-about 95% of pharmaceutical composition weight of the present invention.
Correspondingly, pharmaceutical composition of the present invention comprises sulphur replacement phosphinic acid compounds activeconstituents or its mixture of about 15-95%; The flavouring agent of 0-2%; The cosolvent of 0-50%; The buffer system of 0-5%; The tensio-active agent of 0-2%; The 0-2% sanitas; The sweeting agent of 0-5%; The sticky agent of 0-5%; The weighting agent of 0-75%; The lubricant of 0.5-2%; The antiseize paste of 1-5%; The 4-15% decomposition agent; The tackiness agent of 1-10%.
Basically the administering mode that depends on phosphinic acid compounds corresponding to the selection of the drug excipient that uses with sulphur replacement phosphinic acid compounds of the present invention.If compound is by drug administration by injection, preferred pharmaceutical carrier is aseptic physiological saline, and its pH value is adjustable to about 7.4.But the preferred modes of phosphinic acid compounds of the present invention is oral, thereby preferably presented in unit dosage form is a tablet, and capsule etc., per unit dosage form comprise the di 2 ethylhexyl phosphonic acid compound that provides of the about 600mgP of 0.1mgP-herein.Be applicable to that the pharmaceutical carrier of unit dosage form of preparation oral administration is known in the art.The selection of these carriers will be depended on other some factor that need consider such as sense of taste, cost and storage stability, and these are not vital to the present invention, and those of ordinary skill in the art also is easy to prepare them.
Term used herein " mgP " is meant the weight that is present in the phosphorus atom in a certain amount of di 2 ethylhexyl phosphonic acid compound of the present invention.This unit is used for standard and is used for the quantity and the method for the present invention of the di 2 ethylhexyl phosphonic acid compound of pharmaceutical composition invention.For example, [(5-[(2-sulfydryl-1-oxa-third amino (oxopropylamino)-2-pyridyl] aminomethylene] molecular weight of two (phosphonic acids) is 371g/mol, wherein 16.7%(62g/mol) belong to two phosphorus atom in this molecule.Thereby this compound of 1mg has 0.17mgP(1mg * 16.7% as calculated).So in order to prepare the pharmaceutical composition that comprises this compound of 1mgP, said composition should comprise the compound of 6Mg; For the patient that gives a 50Kg with this compound of 1mgP/Kg dosed administration, this patient should be by this compound of administration 300mg.The medicine acceptable carrier that is used for using with phosphonic acids of the present invention is to use with a concentration that is enough to make the gained medicine be suitable for actual use.All things considered, preferred agents acceptable carrier can account for about 0.1%-about 99.9% of total composition weight; More preferably about 20%-about 80%.
The appropriate drug composition is described in following embodiment J-L.Very clear, those of ordinary skill in the art can change following non-limiting examples to form the pharmaceutical composition of wide region.
With calcium and phosphatic abnormal metabolism is the treatment of diseases and the prevention method of feature
Treatment of diseases and prevention method that another aspect of the present invention is is feature with calcium and phosphatic unusual Dai Fangxie.This method comprise to human or other Mammals of needs treatments with of the present invention effectively and the di 2 ethylhexyl phosphonic acid compound administration of safe dose.
Preferred administering mode is oral, but other known medication also can change worry, as mucocutaneous administration (skin for example, administering modes such as rectum) and administered parenterally (for example, by subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection etc.), in inhalation is also included within.Therefore, concrete administering mode includes but not limited to: oral, and skin, mucous membrane, the hypogloeeis, intramuscular, intravenous, endoperitoneal and subcutaneous administration and partial using.
Term used herein " calcium and phosphatic abnormal metabolism " be meant (1) because of calcium and phosphatic abnormal flow effect causes common or special deossification or in body fluid too high calcium and phosphate content be the illness of feature; (2) by calcium and the phosphoric acid salt illness that abnormal deposition caused or produced in vivo.First kind illness includes but not limited to osteoporosis, Paget's disease, and hyperparathyroidism, the virulent hypercalcemia, ectopic ossification and molten bone bone shift.The second class illness includes but not limited to the ossified progress of myositis, calcinosis and other excruciating slight illness physically and mentally.As sacroiliitis, rheumatoid arthritis, osteoarthritis, neuritis, bursitis, tendonitis and other be predisposing to comprise the diseases related that deposits calcium and phosphoric acid salt organizationally and cause.
Term used herein " rheumatoid arthritis " be meant do not know absorption in the cause of disease chronic with the arthritis illness.Its feature is to destroy joint cartilage, ligament, tendon and bone.
Term used herein " osteoarthritis " is meant the non-inflammatory disease in mobilizable joint.Its feature is to worsen and the wearing and tearing joint cartilage; New bone forming with the articular surface place.
Term used herein " dangerous patient " and " need treatment patient " are meant that those are as people or other Mammals that can bear serious calcium and phosphatic abnormal metabolism danger without treatment be subjected to calcium after diagnosing and people or other Mammals that phosphatic abnormal metabolism is being stranded.For example, postmenopausal women is carried out the people of certain steroid therapy; Take the people of anticonvulsion medicine; Paget's disease is arranged after diagnosing, hyperparathyroidism, the people of illnesss such as pernicious hypercalcemia or the transfer of molten bone bone; Suffers from one or more the people in the various forms of osteoporosis after diagnosing; Belonging to than common people has more opportunity to get the people of osteoporosis, as postmenopausal women, and the man over 65 years old, and the people who causes the osteoporosis side effect with more known pharmacological agenies; The people who suffers from the ossified progressive or physical and mental calcinosis of myositis after diagnosing; Be subjected to some other ailing people who torments, these slight illness are sacroiliitis, osteoarthritis, neuritis, bursitis, tendonitis with other predisposing comprise with deposit organizationally calcium and phosphoric acid salt relevant and the pathological condition of inflammation.
The consumption that term used herein " safe and effective amount " is meant compound of the present invention or composition is passed judgment on the scope planted agent enough greatly improving the illness of desire treatment significantly at rational medicine, but enough little of to avoid producing severe side effect (rational benefit/risk ratio).The safety of di 2 ethylhexyl phosphonic acid compound of the present invention and significant quantity can change because of various factors, these factors comprise: the concrete illness that treat, patient's age and physical appearance, the severity of disease, the time length of treatment, other factors in the therapeutic modality of Cai Yonging simultaneously, concrete pharmaceutically-acceptable excipients that the concrete phosphonate (or ester) that is adopted is adopted and doctor in charge's knowledge and experience scope.Once agent can be the about 3500mgP of about 0.01mgP-, and the about 70mgP(of the about 0.0002-of perhaps every Kg body weight is with the 50Kg batheroom scale).Preferably dose can be the about 600mgP of about 1mgP-, or the about 12gP(of the about 0.02-of every Kg body weight is with the 50Kg batheroom scale).But every day dosage height to 4 dosage.Every day, dosage can not produce desirable effect above 500mgP/Kg, may cause undesirable side effect on the contrary.Certainly, for the oral administration situation since absorb limited, thereby in above-mentioned scope domestic demand with higher dosage.
Following embodiment further describes and represents embodiment preferred in the scope of the invention.These embodiment only are used for illustrating the present invention, and not as limitation of the present invention; This is because its various variation patterns all can not break away from spirit scope of the present invention.
Embodiment A
[(5-(3-sulfydryl propyl group)-2-pyridyl) aminomethylene] two (phosphonic acids) synthetic
Prepare and synthesize above-claimed cpd by following process
I. synthetic [(5-bromo-2-pyridyl) aminomethylene] two (phosphonic acids] tetra-ethyl ester
Having still head to collect in the alcoholic acid round-bottomed flask in the entire reaction course, 2-amino-5-smells pyridine (12.5g, 72mmol), triethyl orthoformate (79.2mmol) and diethyl phosphite (158.4mmol) are 140 ℃ of heating, heat after 8 hours, reaction mixture, concentrating under reduced pressure then.The product that the dichloromethane solution of the Virahol by 5% obtains wanting through flash chromatography on silica gel.
II. synthetic [(5-(3-hydroxypropyl-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
To the THF(10mmol that is chilled to [(5-bromo-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester (10mmol) of-78 ℃) in 30 minutes, add the hexane solution of n-Butyl Lithium (2.1 equivalent) in the solution.Keep reaction 30 minutes again at-78 ℃.In this solution, add 3-iodine propyl alcohol trimethyl silyl (TMS) ether (2.5 equivalent), make to be reflected in 30 minutes heat to room temperature.After standard water is handled, after (work-up), isolate [(5-(3-hydroxypropyl, TMS ether)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester, not purifiedly be used for next step reaction.
By in THF, stirring above-mentioned product and in 30 minutes, realizing TMS ether dissociating from product by dripping adding tetrabutylammonium (the THF solution of 1M) solution.After standard water is handled,, can be directly used in next step by the time be separated into the buttery primary alconol.
III. synthetic [(5-(3-bromopropyl)-2-pyridyl) aminomethylene] two (phosphonic acids)] tetra-ethyl ester
At room temperature stir [(5-(3-hydroxypropyl-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester (10mmol), carbon tetrabromide (11mmol) and the mixture of triphenyl phosphine (11mmol) in methylene dichloride (100ml) 5 hours.To wherein adding water, the product dichloromethane extraction.Drying also concentrates the combination organic extract, and residue obtains [(5-(3-bromopropyl-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester with the flash column chromatography purifying.
IV. synthetic [(5-(3-acetyl thio propyl group-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester.
[(5-(3-bromopropyl-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester.Solution (5.0mmol) stirs in anhydrous propanone (35ml) and adds sodium thioglycolate (5.2mmol).Mixture stirred 12 hours down at 500 ℃.After being cooled to room temperature, remove solvent through decompression.Thick residue is dissolved in the methylene dichloride and washes with water.Dry then organic layer carries out concentrating under reduced pressure again.The product that the dichloromethane solution of use gradient 5-10% Virahol obtains wanting through the flash chromatography on silica gel purifying.
V. synthetic [(5-(3-sulfydryl propyl group-2-pyridyl) aminomethylene] two (phosphonic acids)
Thioacetate (4.2mmol) is at 1NHCl(15ml) in reflux 5 hours.Reaction mixture is used activated carbon treatment, filter, concentrating under reduced pressure, subsequently with the acetone development, and then under vacuum dried overnight, obtain the desired product of suitable purity.
Embodiment B
Synthesizing of [(5-(3-acetyl thio propyl group-2-pyridyl) aminomethylene] two (phosphonic acids)
Figure 931082773_IMG21
Under argon atmospher, make described in [(5-(3-acetyl thio propyl group-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester (above-mentioned example A(III) preparation) and in distilled water reflux preparation in 18 hours [(5-(3-acetyl thio propyl group)-2-pyridyl) aminomethylene) two (phosphonic acids).Decompression concentrates above-mentioned reaction mixture down, obtains product through water and Virahol recrystallization.
Embodiment C
Synthesizing of [(5-sulfydryl-2-pyridyl) aminomethylene] two (phosphonic acids)
Figure 931082773_IMG22
Above-claimed cpd is prepared with following process and synthesizes.
I. synthetic [(5-nitro-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
Having still head to collect in the alcoholic acid round-bottomed flask in the entire reaction course, 2-amino-5-nitropyridine (10g, 71.9mmol), triethyl orthoformate (11.7g, 79.1mmol) and diethyl phosphite (21.86g, 158.2mmol) heating under 140 ℃.After heating 10 hours, reaction mixture, concentrating under reduced pressure then.The product that the dichloromethane solution of the Virahol by 5% obtains wanting through flash chromatography on silica gel.
II. synthetic [(5-amino-2-pyridyl) aminomethylene) two (phosphonic acids) tetra-ethyl ester
[(5-nitro-2-pyridyl) aminomethylene) and two (phosphonic acids) tetra-ethyl ester (5.29g, 12.4mmol), dehydrated alcohol (100mmol) and 10% carbon (1.3g) are gone up palladium and are placed 500mlparr hydrogenation flask, and hydrogenation is 4 hours under 40Psi.Through diatomite filtration reaction response mixture, concentrating under reduced pressure then.Need not to be further purified, the solid of generation just can be used for following processes.
III. synthetic [(5-sulfydryl-2-pyridyl) aminomethylene) two (phosphonic acids) tetra-ethyl ester
Add in the Tetrafluoroboric acid nitrous (NoBF4) under room temperature in dichloromethane fan (6ml) [(5-amino-2-pyridyl) aminomethylene) and two (phosphonic acids) tetra-ethyl ester (75mg, 0.19mmol).Stirred reaction mixture 3 hours, concentrating under reduced pressure then.Crude product is dissolved in the acetonitrile (6ml), and adding sodium sulphite (46mg, 0.19mmol).Stir after 12 hours under the room temperature, add water reaction is stopped, using the dichloromethane extraction mixture.Merge organic extract, use 10%Na 2S 2O 3Solution washing.Organic extract after dried over sodium sulfate, filters concentrating under reduced pressure again.The dichloromethane solution of the Virahol with 2% is through purification by flash chromatography, by the time the thiol moiety of wanting.
IV. synthetic [(5-sulfydryl-2-pyridyl) aminomethylene) two (phosphonic acids)
Backflow tetra-ethyl ester (0.5mmol) obtained two phosphonic acids in 15 hours in the distilled water under nitrogen atmosphere (25ml).The reaction mixture activated carbon treatment is filtered and concentrating under reduced pressure.Crude product water and ethyl alcohol recrystallization and obtain [(5-sulfydryl-2-pyridyl) aminomethylene) two (phosphonic acids).
Embodiment D
[(4-(4 sulfydryl butyl)-2-pyridyl) aminomethylene) two (phosphonic acids) synthetic
Figure 931082773_IMG23
Above-claimed cpd is prepared by following process and synthesizes.
I. synthetic [(4-bromo-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
Use previous embodiment A(I) the basic identical process of describing makes 2-amino-4-bromopyridine and triethyl orthoformate and diethyl phosphite reaction obtain [(4-bromo-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester.
II. synthetic [(4-4-hydroxyl butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
To the THF(10ml that is cooled to [(4-bromo-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester (10mmol) of-78 ℃) in 30 minutes, add n-Butyl Lithium (2.1 is normal) hexane solution in the solution.Under-78 ℃, keep this reaction 30 minutes again.In solution, add 4-iodine butanols trimethyl silyl (TMS) ether (2.5 equivalent), in 30 minutes, reaction is heated to room temperature.After standard water was handled, [(4-(4-butanols, TMS ether)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester was separated, need not purifying and promptly can be used for next step reaction.
By in THF, stirring above-mentioned product and in 30 minutes, realizing the separation of TMS ether from product by dripping adding tetrabutylammonium (the THF solution of 1M).After standard water is handled, obtain being separated into a kind of buttery primary alconol, can be directly used in next step reaction.
III. synthetic [(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
Use the foregoing description A(III and IV) described essentially identical reaction process, make [(4-(4-hydroxyl butyl-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester change into [(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester.
IV. synthetic [(4-(4-sulfydryl butyl)-2-pyridyl) aminomethylene] two (phosphonic acids)
At 1NHCl(20ml) in thioacetate (5.0mmol) be heated and refluxed 8 hours, reaction mixture use activated carbon treatment, filters also concentrating under reduced pressure.Subsequently with acetone development, so under vacuum dried overnight.Obtain the required product of suitable purity.
Embodiment E
[(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) synthetic
[(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) prepare through following process: reflux in the distilled water under the argon atmospher [(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester [pressing the described preparation of the foregoing description D] 18 hours.The concentrating under reduced pressure reaction mixture obtains product through the recrystallization of water and Virahol.
Embodiment F
[(5-[(2-sulfydryl-1-oxopropyl) amino]-2-pyridyl) aminomethylene] two (phosphonic acids) synthetic
Figure 931082773_IMG25
Above-claimed cpd is through following process preparation and synthetic.
I. synthetic [(5-[(2-sulfydryl-1-oxopropyl) amino]-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester
0 ℃ with thiolactic acid (1.95g 18.38mmol) is added in coupler 1-(3-dimethyl aminopropyl in the methylene dichloride (15ml) lentamente)-3-ethyl carbodiimide hydrochloride (3.52g, 18.38mmol) in.Then [(5-amino-2-pyridyl) aminomethylene] two (phosphonic acids) tetra-ethyl ester in wherein adding methylene dichloride (10ml) product of described preparation [the foregoing description C(II)] (4.84g, 12.25mmol).Stirred reaction mixture is 24 hours under the nitrogen atmosphere room temperature.With methylene dichloride (150ml) diluted reaction mixture, ((1 * 125ml) washing of the saturated NaCl aqueous solution is used in 2 * 150ml) washings to water more again.The organic layer dried over sodium sulfate is filtered and concentrating under reduced pressure.It is 52% yellow oil product (3.05g) that the dichloromethane solution of the Virahol by 5% obtains productive rate through flash chromatography on silica gel purifying acid amides.
II. synthetic [(5-[(2-sulfydryl-1-oxopropyl) amino]-2-pyridyl) aminomethylene] two (phosphonic acids)
Under the nitrogen atmosphere room temperature, with the bromo trimethyl silane in chloroform (25ml) (5.80g, 37.89mmol) handle two phosphonic acids tetra-ethyl esters (3.05g, 6.31mmol).Add methyl alcohol and make the reaction mixture stopped reaction, then this product of concentrating under reduced pressure.Crude product is developed with ethyl acetate, and then high vacuum dry, obtains two phosphonic acids (2.34g) light yellow solid of productive rate 100%.
Embodiment G
[2-acetyl thio-2-(3-pyridyl) ethylidene] two (phosphonic acids) synthetic
Figure 931082773_IMG26
Above-claimed cpd is through following process preparation and synthetic.
I. synthetic 4,4 '-(3-pyridyl methylene radical) two morpholines
Comprise 3-pyridine carboxy aldehyde (Carboxaldehyde) (3.97g, 37.09mmol), boron trioxide (4.31g, 61.94mmol) and morpholine (7.76g, the suspension of benzene 89.02mmol) (10ml) at room temperature stirred 2 hours.To remove the hydration boron compound, filtrate obtains the good bisaminal(7.17g of productive rate 73% purity through concentrating under reduced pressure through the diatomite filtration reaction mixture).
II. synthetic [the 3-(2-pyridyl) vinylidene] two (phosphonic acids) tetra-ethyl ester.
Bisaminal(1.00g in toluene (6ml), add in 3.80mmol) trifluoroacetic acid (0.89g, 7.79mmol).This mixture heated 15 minutes down at 60 ℃, and (1.10g, 3.80mmol), the reaction under 60 ℃ was stirred 22 hours totally to add Tetraethyl diphosphonomethane.Reaction mixture is to wherein adding entry.Two-layer separated opening is with methylene dichloride (3 * 15ml) aqueous layer extracted.Merge organic layer, use dried over sodium sulfate, filter concentrating under reduced pressure.By flash chromatography on the silica gel (97: 3 methylene dichloride/Virahols) two phosphonic esters are separated with the ester of unreacted methylenediphosphonate (MDP) with pyridine carboxy aldehyde, obtain ethene adducts (296mg) light yellow oil of productive rate 20%.
III. synthetic [the 3-(2-pyridyl) vinylidene] two (phosphonic acids)
(1.66g, 4.39mmol) (5.38g 35.12mmol) handled 12 hours with the bromo trimethyl silane in the chloroform at 50 ℃ of following pair of phosphonic esters of nitrogen atmosphere.Water (20ml) and ethyl acetate (20ml) stirred reaction mixture 30 minutes.Double-layer separate is left, and the water layer activated carbon treatment is by diatomite filtration and concentrate two (phosphonic acids) (0.66g) light yellow solid obtain productive rate 57%.
IV. synthetic [2-acetyl thio-2-(3-pyridyl) vinylidene] two (phosphonic acids)
[3-(2-pyridyl) vinylidene] two (phosphonic acids) in water (5ml) (0.56g, add in 2.11mmol) thioacetic acid (0.80g, 10.55mmol).After at room temperature stirring 5 hours, the concentrating under reduced pressure reaction mixture, with the acetone development, and then dry under the high vacuum, by the time two (phosphonic acids) light yellow solids (375mg) of productive rate 52%.
Embodiment H
[2-sulfydryl-2-(3-pyridyl) ethylidene] two (phosphonic acids) synthetic
Figure 931082773_IMG27
Above-claimed cpd is by following process preparation and synthetic.
I. synthetic [2-acetyl thio-2-(3-pyridyl) ethylidene] two (phosphonic acids) tetra-ethyl ester.
(15ml) stirs (3-(2-pyridyl) vinylidene in the room temperature anhydrous chloroform) product of two (phosphonic acids) tetra-ethyl ester (1.0g, 2.65mmol) [previous embodiment G(II) preparation] and thioacetic acid (0.30g, 3.98mmol) 48 hours.Concentrating under reduced pressure reaction mixture then.Residue is dissolved in the acetone, concentrates for the second time under vacuum, by the time the thioacetate of productive rate 83% (1.01g) again.
II. synthetic [2-sulfydryl-2-(3-pyridyl) ethylidene] two (phosphonic acids)
Reflux in concentrated hydrochloric acid [2-acetyl thio-2-(3-pyridyl) ethylenebis (phosphonic acids) tetra-ethyl ester (1.01g, 2.21mmol) the two phosphonic acids of preparation in 3 hours.Evaporating solns is extremely dried down in decompression then.Crude product is dissolved in the warm water, uses activated carbon treatment, passes through diatomite filtration again.Filtrate is used twice of dichloromethane extraction.By adding ethanol product is precipitated out from filtrate.The collecting precipitation thing washs with diethyl ether after filtration, and vacuum-drying in moisture eliminator.
Embodiment 1
[5-sulfydryl-2-(3-) pentylidene] two (phosphonic acids) synthetic
Figure 931082773_IMG28
This compound is by following process preparation and synthetic
I. synthetic 5-hydroxyl-2-(3-pyridyl) Valeric acid ethylester, t-butyldimethylsilyl ether
Anhydrous THF(125ml under-78 ℃ of argon atmosphers) LDA (4.60mmol) in the 3-Pyridineacetic Acid ethyl ester in (0.76g adds THF(25ml in solution 4.60mmol)).-78 ℃ of following stirred solutions 30 minutes, in solution, add 3-iodine propyl alcohol then, at THF(20ml) in t-butyldimethylsilyl ether (5.00mmol).-78 ℃ of following restir reactions 2 hours, at room temperature stirred then 8 hours.Add saturated aqueous ammonium chloride and make the reaction mixture stopped reaction.With two separate, the water layer extracted with diethyl ether merges organic layer, drying, and concentrating under reduced pressure.Product carries out purifying with the hexane solution of 20% methylene dichloride through flash chromatography on silica gel.
II. Synthetic 2-(3-pyridyl) pentane-1,5-glycol, 5-t-butyldimethylsilyl ether.
The THF(100ml that under nitrogen atmosphere, refluxes) make carboxylicesters be reduced into corresponding alcohol with lithium aluminium hydride (5.50mmol) processing in.Add entry carefully so that reaction stops, handling aluminium salt with rare NaOH aqueous solution subsequently.Through the diatomite filtration reaction mixture, again with two separate, water layer extracts with Anaesthetie Ether.Merge organic layer, dry and under reduced pressure concentrated.The oil that generates need not to be further purified.
III. synthetic 5-bromo-4-(3-pyridyl) amylalcohol, t-butyldimethylsilyl ether
At room temperature stir the 2-(3-pyridyl) pentane-1,5-glycol, 5-t-butyldimethylsilyl ether (10mmol), carbon tetrabromide (11mmol) and the mixture of triphenyl phosphine (11mmol) in methylene dichloride (100ml) 5 hours.Add entry, the product dichloromethane extraction.Merge organic extract liquid and drying and concentrate it.Residue obtains 5-bromo-4-(3-pyridyl through the flash column chromatography purifying) amylalcohol, t-butyldimethylsilyl ether.
IV. synthetic 5-hydroxyl-2-(3-pyridyl) the amyl group diethyl phosphonate, t-butyldimethylsilyl ether
Heat 5-bromo-4-(3-pyridyl down at 90 ℃) amylalcohol, the solution of t-butyldimethylsilyl ether (0.75mmol) and triethylphosphine (1.12mmol) 72 hours keeps nitrogen gas stream by reaction in the heat-processed.Remove three excessive methylphosphines by distillation, the thick residual thing that heats up in a steamer is handled through silica gel chromatography with the dichloromethane solution of 2% Virahol.Product need not to be further purified and can be used for following reaction process.
V. synthetic [5-hydroxyl-2-(3-pyridyl) pentylidene] two (phosphonic acids) diethyl ester, the dimetylsilyl ether of the tertiary butyl
Under 0 ℃, to 5-hydroxyl-2-(3-pyridyl) the amyl group phosphonic acids, diethyl ester, the anhydrous THF(200ml of the dimetylsilyl ether (15.0mmol) of the tertiary butyl) add s-butyl lithium (33.0mmol, the cyclohexane solution of 1.3M) in the solution.Continue subsequently to stir 30 minutes.At room temperature in solution, add chloro diethyl phosphoric acid (2.50g, anhydrous THF(100ml 14.47mmol)) solution then lentamente.After stirring reaction spent the night, the saturated aqueous solution that adds sodium bicarbonate made the mixture stopped reaction, extracts with methylene dichloride then.The organic extract liquid anhydrous sodium sulfate drying that merges filters and under reduced pressure concentrates.Crude product with the hexane solution of 30% acetone through the flash chromatography on silica gel purifying.
VI. synthetic [5-hydroxyl-2-(3-pyridyl) pentylidene] two (phosphonic acids) diethyl ester
At room temperature use tetrabutylammonium (0.75mmol) to handle ether (0.50mmol) 30 minutes among the THF to decomposite silyl ether.Fully behind the deprotection, with saturated NaCl solution washing reaction mixture.Use the dried over sodium sulfate organic layer, filter concentrating under reduced pressure.Obtaining the available residue need not to be further purified.
VII. synthetic [5-bromo-2-(3-pyridyl) pentylidene] two [phosphonic acids] diethyl ester
Use the essentially identical process of aforementioned part III, will [5-hydroxyl-2-(3-pyridyl) pentylidene) two (phosphonic acids) diethyl ester changes into [5-bromo-2-(3-pyridyl) pentylidene] two (phosphonic acids) diethyl ester.
VIII. synthetic [5-acetyl thio-2-(3-pyridyl) pentylidene] two (phosphonic acids) diethyl ester
In anhydrous propanone (35ml), stir the solution of [5-bromo-2-(3-pyridyl) pentylidene] two (phosphonic acids) diethyl ester, and add sodium thioglycolate (5.2mmol).Mixture stirred 12 hours down at 50 ℃.After being cooled to room temperature, decompression removes solvent.Thick residue is dissolved in methylene dichloride, washes with water.Dry then organic layer, concentrating under reduced pressure.The product that obtains wanting carries out purifying through flash chromatography on silica gel with the dichloromethane solution gradient of the isopropyl acetone of 5-10%.
IX synthetic [5-sulfydryl-2-(3-pyridyl) pentylidene] two [phosphonic acids]
Will [5-2 acyl sulfo--2-(3-pyridyl) pentylidene] two [phosphonic acids] diethyl ester (4.2mmol) be dissolved in 2.5MHCL(65ml) in, reflux 7 hours.Reaction mixture and concentrating under reduced pressure.Solid residue is developed with acetone, then water and ethyl alcohol recrystallization obtain [5-sulfydryl-2-(3-pyridyl) pentylidene two [phosphonic acids]
Embodiment J
The ScheNK model
With the animal model system that is referred to as the SchenK model in the bone metabolism field The compounds of this invention is carried out bone resorption inhibition and mineralising inhibition assessment in the body.The rule of this model system is open in following document: Shinoda etc., and Calcif, Tissue Int, 35,87-99(1983); Calcif such as Schenk, Tissue Res, 11,196-214(1973), above-mentioned document is introduced here with for referencial use.
Raw material and method
Animal
The male Sprague Dawley rat (chanles River Breeding Laboratories) of preceding 17 days (30 gram) of weaning is loaded and transported with its mother, and places the plastics cage until arriving experimental field with its mother it.When growing to 19 days, the young mouse random assignment that will feed mouse food (Rat Chow) and water becomes treatment group or control group, and every group comprises 7 young mouse.At the 1st day and the 7th day twice, (1% solution in 0.9% salt brine solution, dosage were the 0.2ml/100g body weight to all young mouse intraperitoneal (" IP ") injection fluorexons.The 4th day, give all animal IP injection tetracycline hydrochloride (solution of 1% in 0.9% salt brine solution; Dosage is the 0.2ml/100g body weight).These compound activity mark mineralising bone and cartilages.
Dosage solution and dosage method
All solution are mixed with the subcutaneous injection reagent in 0.9% physiological saline and use NaoH and/or HCl adjusting pH value to 7.4.Dosage solution is with the mg/Kg(body weight) expression active material powder quality (is benchmark with the hydrate molecule amount) carry out, mg/Kg is corresponding to mgP/Kg.Concentration is to be benchmark with 0.2ml/100g body weight dosage.Usually, in 7 days, all compounds are with 0.01,0.1,1.0 and administration in 10.0mgP/Kg/ days.Show that at 0.1mgP/Kg/ days active compound tests to 0.001mgP/Kg/ days with logarithmic decrease.The benchmark that is changed to of body weight is regulated dosage with every day.
Ptomatopsia, tissue processing and tissue morphology measurement
Beginning to take medicine back the 8th day, and all animals were being caused death by injecting excessive Sodital (Penta batol).Dissect shin bone, be placed in 70% the ethanol.A shin bone dewaters with the fractionated ethanolic soln, and is placed in the methyl methacrylate, and (G.R.DicKson compiles as described in the method for Schenk among the Caleified Tissue Preparation; Elsevitr Science publishes, Holland, 1984), the document is introduced here with for referencial use.Shin bone is by the vertical cutting method of metaphyseal region.A surface cma staining of sample places use Quantimet Image Analyzer(Cambridge Instruments on the slide with sample, Inc) assesses with incandescent and uv irradiating.Metaphyseal trabecular bone content measures and is expressed as the per-cent of the total area (bone+marrow) with zone between fluorescent mark and growth plate.The growth plate width of epiphysis is 10 mean values that wait the space measurement value of entire cross section.
Operation parameter and non-parametric variance analysis and the test of wilcoxons sum of ranks are carried out the statistical estimation of data to determine than the statistical positive effect of control animal.
The Schenk model provides The compounds of this invention to be used for the data that bone resorption suppresses in the body.Provided minimum effectively (the anti-absorption) dosage " LED " of the representational compound of determining by the Schenk model of being tested in the table 2.
Embodiment K
The scorching model of subjoint
Arthritic animal model has many kinds, a kind of helper-inducer model that is to use MycobacteRiumbutyRium wherein.This model is simulated the rheumatoid arthritis of human body in many ways and (is invaded relevant arthroncus, bone resorption and enter joint space chemotaxis factor and the release (1,2) of lysosome structure branch with the cell and the pannus of joint space.Many preventions and treatment research have shown that anti-inflammatory drug (3,4) and di 2 ethylhexyl phosphonic acid (5,6) when arthritis treatment, can effectively use.
Reference
Pearson，C.，Wood F.（1959），Studies of Polyarthritis and Other Lesions Induced by Injection of Mycobacterial Adjuvant.1.General Clinical and Pathological Characteristics and Some Modifying Factors，Arth.Rheum.，2：440-459.
Blackman，A.，Burns，J.W.，Framer，J.B.，Radziwonik，H.，Westwick，J.（1977），An X-ray Analysis of Adjuvant Arthritis in the Rat.The Effect of Prednisolone and Indomethacin，Aqents and Actions，7：145-151.
Winter，C.A.，Nuss，G.W.（1966），Treatment of Adjuvant Arthritis in Rats with Anti-inflammatory Drugs，Arth.Rheum.，9：394-404.
Winder，C.V.，Lembke，L.A.，Stephens，M.D.（1969），Comparative Bioassay of Drugs in Adjuvant-Induced Arthritis in Rats：Flufenamic Acid，Mefenamic Acid，and Phenylbutazone，Arth.Rheum.，12：472-482.
Francis，M.D.，Flora，L.King，W.R.（1972），The Effects of Disodium Ethane-1-Hydroxy-1-Diphosphonate on Adjuvant Induced Arthritis in Rats，Calcif.Tiss.Res.，9：109-121.
Flora，L.（1979），Comparative Antiinflammatory and Bone Protective Effects of Two Diphosphonates in Adjuvant Arthritis，Arth.Rheum，22：340-346.
The sacroiliitis that medicament brings out is a kind of serious phlegmon and synovitis.They carried out once subcutaneous (SC) at the 0th day to male rat (Sprague Dawley or Lewis Strain) and are injected at Mycobacterium butyricum(8mg/ml in the mineral oil) bring out, take compound of the present invention by oral (PO) or parenteral (SC) once a day, and it is tested with prevention (from the 0th day) or treatment (from the 9th or 10 or 14 day) test.Arthritis usefulness comparability in the sacroiliitis of brine treatment in the same old way, with corpus unguis long-pending reduce, body weight loss/bone loss or react new bone forming and measure.Can stop treatment and detect " sudden illness " response (increasing sharply of inflammatory), this response shows that compound keeps the ability of usefulness.
Raw material and method
The A animal
What use animal is male Lewis rat (LEW).After animal transports to, it is carried out random sampling by the random number that computer produces, and be placed in the cage of single individual line suspention.During whole research, optionally subsist or water.Carry out the routine of animal takes care of and maintenance according to state and articles of confederation.Each rat is with placing the number of each cage front and mouse tail to discern.
The B experimental design
First day, body weight (BW) and the rear solid end volume (PV) of all rats are measured.[be to use the sensator that is connected with computer to write down (PV) by the mercury displacement method).The 0th day, use MFA[Mycobacterium butyricum(Mb) with 4.4mg/Kg in oil) induce arthritic process as follows:
Make rat anesthesia and under aseptic condition, inject MFA at the disposable SC of mouse tail end.
Corpus unguis is long-pending to be measured every several days with body weight, and a common week surveys twice.To prophylactic tria, rat is distributed into one group of 8～10 mouse randomly, from the 0th day begin treatment and continue every day to carry out to finish until experiment.To therapeutic test, rat becomes the treatment group of one group of 8～10 mouse by its PV random assignment of the 10th day.Beginning administration in the 10th day, every day, successive administration was until off-test.Concerning two kinds of tests, before the 10th day or the 10th day, animal is placed in the footwear box cage with dark bottom.
Dosage solution
Compound for impossible oxidation
Medicine is weighed on the balance of calibration at one, then it is mixed in a capacity flask with distilled water.Regulate pH value to 7.4 with 0.1N NaOH.Solution filters with the sterile filters of 0.45 μ m it is entered in the aseptic storage container then.When not using, it is stored in the refrigerator.
Compound for the possibility oxidation
Medicine is weighed on the balance of calibration at one, it is mixed in a capacity flask with de-oxygenised water.Stock solution filtered with the sterile filters of 0.45 μ m it is entered in the aseptic storage container.When not in use, it is stored in the refrigerator.
With every day consumption be benchmark, certain quantity solution is taken out from stock solution, put it in the less beaker of volume, according to the predetermined computation value pH value of solution is adjusted to 7.4.If necessary can be with the solution dilution of regulating (using de-oxygenised water).
Medication dosing is that the purity with molecular weight and compound is that benchmark calculates, its consumption is with the mg/Kg(body weight) be that benchmark calculates, required final concentration is represented with mgP/Kg, when the inguinal fold folding place of animal subcutaneous injection, the dosage of each rat is the 0.1ml/100g body weight, and wherein injection should hocket every other day at pleat folding place, both sides.Another kind of administering mode is to use crooked stainless steel dosage pipe with the 1ml/200gBW oral administration.Adjust consumption with body weight change weekly.
Radiograph, ptomatopsia and tissue collecting
When administration finished, each rat was used 1ml Socomb
Figure 931082773_IMG29
Cause death through peritonaeum (IP).Immediately by Torrox 120DX ray unit at MA=5, ISUP=50, the time is under 60 seconds the condition whole health to be carried out the shooting of radiograph, taking a picture, what use is that Kodak does not have the medicinal film of net.The back leg of each mouse cutd open down and and a slice liver,kidney,spleen and thimus together.Place 10% buffered formalin, articulatio tibiotarsalis is at 4%EDTA(PH7.4) in decalcification and in paraffin mass and H+E stain, make conventional processing.The organ part is also handled in paraffin and stain H+E.
Use microscope bone and soft tissue injury to be organized the qualitative evaluation of section.For bone resorption (BR), the deciding grade and level of radiograph is to dissect the trabecular bone site with 6 of each back legs to carry out with 4 sites of each foreleg, and 4 legs are characterized 0～60 estimated score with 0～3 grade.To reacting new bone forming (RNB), radiograph is decided to be strength grade 0～3 to the outside and the internal surface of shin bone, be 0-2 to above-mentioned all other zone definitions, thereby estimated score is 0～44.
The D statistical study:
Long-pending to corpus unguis, bone resorption and the new osteoplastic data analysis of reaction are by student's t-test and Tukeys(SAS) step analysis of (12) variance carries out.Be considered to tangible at P=0.05 or littler time error.
This model provides the interior data of body of explanation arthritis compound usefulness to compare with the arthritic animal of brine treatment, and the pawl swelling bone that this usefulness reduces loses and react the formation of new bone.
Embodiment L
The capsule that comprises following composition according to the ordinary method preparation:
Activeconstituents mg/ capsule
[5-sulfydryl-2-350.0
(3-pyridyl) inferior penta
Base] two [phosphonic acids]
Vehicle
Lactose 90.0
Microcrystalline Cellulose 60.0
Magnesium stearate 1.0
Capsule with above-mentioned composition uses ordinary method preparation as described below:
Activeconstituents mixed in cylindrical blender about 10 minutes with Microcrystalline Cellulose.
The mixture that makes is by a hammer mill that has 80 mesh sieves.
This mixture turned back in two mixing machines remix about 15 minutes with lactose.
Added magnesium stearate and remix again 5 minutes.The mixture that makes is then suppressed on piston one activatory capsule filling machine.
Embodiment M
Preparation has the tablet of following composition:
Activeconstituents mg/ sheet
[2-sulfydryl-2-700.0
(3-pyridyl) inferior second
Base] two [phosphonic acids]
Vehicle
Lactose (spray-dired) 200.0
Starch (1500) 100.0
Magnesium stearate 25.0
Have of the method preparation of the tablet of above-mentioned composition according to following routine:
Ground active ingredient about 30 minutes in ball milling, the lactose after the activeconstituents that ground and the spraying drying mixed in two slurry mixing tanks about 20 minutes.
In mixture, add starch, remix 15 minutes.On the standard tabletting machine with the mixture tablet forming.
To twice of patient every day of the about 70Kg of body weight that suffers from Paget's disease with above-mentioned tablet oral administration, continue to reduce basically in 6 months bone resorption.When using following compound to replace [2-sulfydryl-2-(3-pyridyl) ethylidene] two [phosphonic acids] of above-mentioned tablet, obtained similar result: [(5-(3-sulfydryl propyl group)-2-pyridyl) aminomethylene] two [phosphonic acids]; [5-(3-acetyl sulphur substituted propyl)-the 2-pyridyl) aminomethylene] two [phosphonic acids]; [(5-sulfydryl-2-pyridyl) aminomethylene] two [phosphonic acids]; [(4-(4-acetyl thio butyl)-2-pyridyl) aminomethylene] two [phosphonic acids]; [(4-(4-sulfydryl butyl)-2-pyridyl) aminomethylene] two [phosphonic acids]; But or the patent medicine salt or the ester of these phosphinic acid compounds.
Embodiment N
According to the solution that the ordinary method preparation is suitable for injecting, the normal saline solution of use 10.0ml and 7.0mgP [2-sulfydryl-2-(3-pyridyl) ethylidene] two [phosphonic acids], regulate PH=7.4.
Patient to the pernicious hypercalcemia of the about 70Kg of body weight injected four days once a day altogether, and symptom obviously alleviates as a result.
Embodiment O
About 92Kg of body weight, 72 years old, right knee suffer from medium to the severity pain and the Caucasia male patient of swelling also occasionally.Through after about discomfort that constantly increased the weight of in a year, he goes for a doctor, and the clinical diagnosis that this doctor does is that right knee suffers from the osteoarthritis disease, with after radiodiagnosis make a definite diagnosis.
Comprise the improvement treatment of Asprin, naprosen and Ketopprofen through various NSAIDs after a while, his illness continues to worsen, and his situation is obviously degenerated.He goes to have seen his doctor again, and doctor formula is taken the described tablet that makes of embodiment M by it, and ante cibum and meal latter two hour take, and also continued three months twice of every day.Through trimestral treatment, his the painful disease and the clinical symptom of swelling, the symptom when particularly spreading to walking is significantly improved.At three months, capsule administration with the described preparation of example R once a day continued treatment afterwards and carries out, but dosage is former dosage (as capsule every day) half.
Embodiment P
An about 65Kg age of body weight is swelling of 55 years old both hands articulations digitorum manus and distortion, and its finger and hand portion have been lost the Black women of intensity and/or susceptibility.Through visual and X～ray detection and American Rheumatological Association(ARA) the various suitable clinical trial confirmed, prove conclusively her and suffer from rheumatoid arthritis.
Through once unsuccessful pain relieving and anti-inflammatory treatment, her doctor allows it take the tablet that example M makes, and every day twice, takes in ante cibum or two hours after meal and continues 4 months.Through one month treatment, the symptom of her dactylus swelling was significantly improved, and the scope of activity of its finger also obviously increases; She continues the treatment on its four months remaining dates, after, her doctor continues to allow it continue treatment two months by aforementioned dosage.
Example Q
A Hispanic women (12 years old, the about 37Kg of body weight) states the rheumatoid arthritis of teenager's property that it is spontaneous Xiang the doctor.Her symptom comprises the serious inflammation in most joints, and fever and tenderness, shows the decline of the rapid and pathology of function of joint.
Her doctor advises that she goes to see a rheumatosis expert, and this expert has worked out the positive therapeutic scheme immediately, and to its solution IV administration with the described preparation of example N, inject once every day in 3 days, and the per injection administration time was above 2 hours.When the IV treatment finished, the doctor took in ante cibum or two hours after meal to tablet, every day that she has opened the described preparation of example N obeying twice, and continued 2 months, and during this period, her symptom is obviously improved, and joint mobilization increases, pain relief.Through after two months, reduce dosage to 3/4 of original dosage again, clothes were 3 in per two days, and for example, two capsules became one day capsule in one day.Through current treatment, dosage is kept to 1/4 of original dosage once more, promptly allows it take the capsule of the described preparation of example L, and every day, a capsule was taken four months again.

Claims (29)

  1. But 1, a kind of nitrogenous heterocyclic phosphinic acid compounds of sulphur replacement or the phosphonate or the ester of its patent medicine, its structural formula is as follows:
    Figure 931082773_IMG2
    Wherein m and n are the integer of 0-10, and m+n equals 0～10.
    (a) Z is monocycle or encircles heterocyclic moiety more, and it comprises and is selected from O, and one or more heteroatomss among S or the N wherein have at least one to be N;
    (b) Q is a covalent linkage, S, O, N or NR 1
    (c) R is PO 3H 2Or (OH) R of P (O) 4, R wherein 4For replacing or unsubstituted C 1-C 8Alkyl;
    (d) each R 1Be independently selected from :-SR 6-R 8SR 6Do not exist; Hydrogen; Unsubstituted or replace C 1-C 8Alkyl; Unsubstituted or replace aryl; Hydroxyl;-CO 2R 3-O 2CR 3-NR 3 2-OR 3-N (R 3) C (O) R 3-C (O) N (R 3) 2Replace or unsubstituted benzyl; Nitro or their mixture;
    (e) R 2Be the substituting group on the Z atom partly, it is independently selected from :-SR 6-R 8SR 6-CO 2R 3-O 2CR 3-NR 3 2-N (R) 3C (O) R 3-OR 3-C (O) N (R 3) 2There are not hydrogen, the not C that replaces or replace 1-C 8Alkyl, the not aryl that replaces or replace; Hydroxyl; Replace or unsubstituted benzyl; Nitro; Or their mixture;
    (f) each R 3Be independently selected from: hydrogen; Replace or unsubstituted C 1-C 8Alkyl; Or R 8SR 6
    (g) R 5Be selected from :-SR 6R 8SR 6Hydrogen; Hydroxyl; Amino; Halogen; The C that does not replace or replace 1-C 8Alkyl;
    (h) R 6Be H;-C (O) R 7-C (S) R 7-C (O) N (R 7) 2-C (S) N (R 7) 2-C (O) OR 7Or-C (S) OR 7R wherein 7Be hydrogen, not the C that replaces or replace 1-C 8Alkyl;
    (i) R 8For replacing or unsubstituted C 1-C 8Alkyl; R 1, R 2, R 3Or R 5In have at least a palpus to be SR 6Or R 8SR 6
  2. 2, by the compound of claim 1, wherein Z is for being the monocyclic heterocycles part.
  3. 3, by the compound of claim 2, wherein Z is a hexa-member heterocycle.
  4. 4, by the compound of claim 3, wherein Z is pyridine, pyrimidine, piperidines and dihydropyridine.
  5. 5, by the compound of claim 4, wherein Z is a pyridine.
  6. 6, by the compound of claim 2, wherein Z is a five-membered ring.
  7. 7, by the compound of claim 6, wherein Z is an imidazoles, thiazole ， oxazole, pyrroles, furans, thiophene or tetramethyleneimine.
  8. 8, by the compound of claim 1, wherein Z is many ring heterocyclic moieties.
  9. 9, by the compound of claim 8, wherein Z is the six-ring that is fused on the five-ring.
  10. 10, by the compound of claim 8, wherein Z is for being fused to six-ring on the six-ring.
  11. 11, by the compound of claim 1, wherein Q is N or NR 1
  12. 12, press the compound of claim 1, wherein R 1For being independently selected from :-SR 6;-R 8SR 6; Hydrogen; Replace or unsubstituted C 1-C 8Alkyl;-NR 3 2; Or-CO 2R 3
  13. 13, press the compound of claim 12, wherein R 1For-SR 6, R 8SR 6; Hydrogen.
  14. 14, press the compound of claim 1, wherein R 2For-SR 6, R 8SR 6; Hydrogen; Replace or unsubstituted C 1-C 8Alkyl;-NR 2 3Or-CO 2R 3
  15. 15, press the compound of claim 14, wherein R 2For-SR 6; R 8SR 6Or hydrogen.
  16. 16, press the compound of claim 1, wherein R 3Be hydrogen or R 8SR 6
  17. 17, press the compound of claim 12, wherein R 3Be hydrogen or R 8SR 6
  18. 18, press the compound of claim 14, wherein R 3Be hydrogen or R 8SR 6
  19. 19, press the compound of claim 12, wherein R 6Be hydrogen ,-C(O) R 7; C(S) R 7Or C(O) N(R 7) 2
  20. 20, press the compound of claim 19, wherein R 6Be H;-C(O) R 7; Or C(S) R 7
  21. 21, press the compound of claim 19, wherein R 6Be H;-C(O) R 7; C(S) R 7Or C(O) N(R 7) 2
  22. 22, press the compound of claim 19, wherein R 6Be H;-C(O) R 7; C(S) R 7Or C(O) N(R 7) 2
  23. 23, press the compound of claim 14, wherein R 6Be H;-C(O) R 7; C(S) R 7Or C(O) N(R 7) 2
  24. 24, a kind of pharmaceutical composition, it comprises the compound and the pharmaceutically-acceptable excipients of the claim 1 of safe and effective amount.
  25. 25, by the composition of claim 24, it comprises 0.1%-99.9%(weight) the compound of claim 1.
  26. 26, by the composition of claim 25, it comprises 20%-80%(weight) compound of the present invention.
  27. 27, by the composition of claim 25, it comprises the compound of the claim 1 of 15%-95%; The flavouring agent of 0-2%; The cosolvent of 0-50%; The buffer system of 0-5%; The tensio-active agent of 0-2%; The 0-2% sanitas; The sweeting agent of 0-5%; The binding agent of 0-5%; The weighting agent of 0-75%; The lubricant of 0.5-2%; The antiseize paste of 1-5% (glidants); The decomposition agent of 4-15% and the tackiness agent of 1-10%.
  28. 28, the compound of claim 1 is used for the treatment of or need prevents application aspect the medicine of the mammiferous illness relevant with the phosphoric acid salt abnormal metabolism with calcium of the human of this kind treatment or other in production, it is characterized in that comprising to the mankind or other Mammals compound administration with the claim 1 of safe and effective amount.
  29. 29, the compound of claim 1 is used for the treatment of or need prevents application aspect human or other mammiferous arthritic medicine of this kind treatment in production, it is characterized in that comprising to human or other Mammals compound administration with the claim 1 of safe and effective amount.
CN93108277A 1992-05-29 1993-05-29 Novel thio-substituted, nitrogen-containing, heterocyclic phosphonate compounds, pharmaceutical compositions, and methods of treating abnormal calcium and phosphate metabolism Expired - Fee Related CN1039327C (en)

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IL105832A (en) 1998-08-16
RU94046146A (en) 1996-11-27
PL175046B1 (en) 1998-10-30
NO944501D0 (en) 1994-11-24
ZA933766B (en) 1994-01-20
US5856314A (en) 1999-01-05
NO944501L (en) 1995-01-27
CN1039327C (en) 1998-07-29
AU666741B2 (en) 1996-02-22
CA2136820A1 (en) 1993-12-09
MX9303249A (en) 1994-05-31
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RU2124019C1 (en) 1998-12-27
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IL105832A0 (en) 1993-09-22
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FI945595A0 (en) 1994-11-28
WO1993024500A1 (en) 1993-12-09
CZ295994A3 (en) 1995-10-18
EP0642521A1 (en) 1995-03-15
KR950701932A (en) 1995-05-17
KR100266484B1 (en) 2000-09-15
NO305398B1 (en) 1999-05-25
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CA2136820C (en) 1997-09-09

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